Amino-substituted imidazopyridazines

ABSTRACT

The present invention relates to amino-substituted imidazopyndazine compounds of general formula (I): in which A, R1, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

The present invention relates to substituted imidazopyridazine compoundsof general formula (I) as described and defined herein, to methods ofpreparing said compounds, to intermediate compounds useful for preparingsaid compounds, to pharmaceutical compositions and combinationscomprising said compounds and to the use of said compounds formanufacturing a pharmaceutical composition for the treatment orprophylaxis of a disease, in particular of a hyper-proliferative and/orangiogenesis disorder, as a sole agent or in combination with otheractive ingredients.

BACKGROUND OF THE INVENTION

The present invention relates to chemical compounds that inhibit MKNK1kinase (also known as MAP Kinase interacting Kinase, Mnk1) and MKNK2kinase (also known as MAP Kinase interacting Kinase, Mnk2). Human MKNKscomprise a group of four proteins encoded by two genes (Gene symbols:MKNK1 and MKNK2) by alternative splicing. The b-forms lack a MAPkinase-binding domain situated at the C-terminus. The catalytic domainsof the MKNK1 and MKNK2 are very similar and contain a unique DFD(Asp-Phe-Asp) motif in subdomain VII, which usually is DFG (Asp-Phe-Gly)in other protein kinases and suggested to alter ATP binding [Jauch etal., Structure 13, 1559-1568, 2005 and Jauch et al., EMBO J25,4020-4032, 2006]. MKNK1a binds to and is activated by ERK and p38 MAPKinases, but not by JNK1. MKNK2a binds to and is activated only by ERK.MKNK1b has low activity under all conditions and MKNK2b has a basalactivity independent of ERK or p38 MAP Kinase. [Buxade M et al.,Frontiers in Bioscience 5359-5374, May 1, 2008]

MKNKs have been shown to phosphorylate eukaryotic initiation factor 4E(eIF4E), heterogeneous nuclear RNA-binding protein A1 (hnRNP A1),polypyrimidine-tract binding protein-associated splicing factor (PSF),cytoplasmic phospholipase A2 (cPLA2) and Sprouty 2 (hSPRY2) [Buxade M etal., Frontiers in Bioscience 5359-5374, May 1, 2008].

eIF4E is an oncogene that is amplified in many cancers and isphosphorylated exclusively by MKNKs proteins as shown by KO-mousestudies [Konicek et al., Cell Cycle 7:16, 2466-2471, 2008; Ueda et al.,Mol Cell Biol 24, 6539-6549, 2004]. eIF4E has a pivotal role in enablingthe translation of cellular mRNAs. eIF4E binds the 7-methylguanosine capat the 5′ end of cellular mRNAs and delivers them to the ribosome aspart of the eIF4F complex, also containing eIF4G and eIF4A. Though allcapped mRNAs require eIF4E for translation, a pool of mRNAs isexceptionally dependent on elevated eIF4E activity for translation.These so-called “weak mRNAs” are usually less efficiently translated dueto their long and complex 5′UTR region and they encode proteins thatplay significant roles in all aspects of malignancy including VEGF,FGF-2, c-Myc, cyclin D1, survivin, BCL-2, MCL-1, MMP-9, heparanase, etc.Expression and function of eIF4E is elevated in multiple human cancersand directly related to disease progression [Konicek et al., Cell Cycle7:16, 2466-2471, 2008].

MKNK1 and MKNK2 are the only kinases known to phosphorylate eIF4E atSer209. Overall translation rates are not affected by eIF4Ephosphorylation, but it has been suggested that eIF4E phosphorylationcontributes to polysome formation (i.e. multiple ribosome on a singlemRNA) that ultimately enables more efficient translation of “weak mRNAs”[Buxade M et al., Frontiers in Bioscience 5359-5374, May 1, 2008].Alternatively, phosphorylation of eIF4E by MKNK proteins mightfacilitate eIF4E release from the 5 cap so that the 48S complex can movealong the “weak mRNA” in order to locate the start codon [Blagden S Pand Willis A E, Nat Rev Clin Oncol. 8(5):280-91, 2011]. Accordingly,increased eIF4E phosphorylation predicts poor prognosis in non-smallcell lung cancer patients [Yoshizawa et al., Clin Cancer Res.16(1):240-8, 2010]. Further data point to a functional role of MKNK1 incarcinogenesis, as overexpression of constitutively active MKNK1, butnot of kinase-dead MKNK1, in mouse embryo fibroblasts accelerates tumorformation [Chrestensen C. A. et al., Genes Cells 12, 1133-1140, 2007].Moreover, increased phosphorylation and activity of MKNK proteinscorrelate with overexpression of HER2 in breast cancer [Chrestensen, C.A. et al., J. Biol. Chem. 282, 4243-4252, 2007]. Constitutively active,but not kinase-dead, MKNK1 also accelerated tumor growth in a modelusing Ep-Myc transgenic hematopoietic stem cells to produce tumors inmice. Comparable results were achieved, when an eIF4E carrying a S209Dmutation was analyzed. The S209D mutation mimicks a phosphorylation atthe MKNK1 phosphorylation site. In contrast a non-phosphorylatable formof eIF4E attenuated tumor growth [Wendel H G, et al., Genes Dev.21(24):3232-7, 2007]. A selective MKNK inhibitor that blocks eIF4Ephosphorylation induces apoptosis and suppresses proliferation and softagar growth of cancer cells in vitro. This inhibitor also suppressesoutgrowth of experimental B16 melanoma pulmonary metastases and growthof subcutaneous HCT116 colon carcinoma xenograft tumors withoutaffecting body weight [Konicek et al., Cancer Res. 71(5):1849-57, 2011].In summary, eIF4E phosphorylation through MKNK protein activity canpromote cellular proliferation and survival and is critical formalignant transformation. Inhibition of MKNK activity may provide atractable cancer therapeutic approach.

WO 2007/025540 A2 (Bayer Schering Pharma AG) relates to substitutedimidazo[1,2-b]pyridazines as kinase inhibitors, particularly PKC(protein kinase C) inhibitors, in particular PKC theta inhibitors.

WO 2007/025090 A2 (Kalypsis, Inc.) relates to heterocyclic compoundsuseful as inhibitors of Mitogen-activated protein kinase(MAPK)/Extracellular signal-regulated protein kinase (Erk) Kinase(abbreviated to “MEK”). In particular, WO 2007/025090 A2 relates interalia to imidazo[1,2-b]pyridazines.

WO 2007/013673 A1 (Astellas Pharma Inc.) relates to fused heterocyclesas inhibitors of Lymphocyte protein tyrosine kinase (abbreviated to“LCK”). In particular, WO 2007/013673 A1 relates inter alia toimidazo[1,2-b]pyridazines.

WO 2007/147646 A1 (Bayer Schering Pharma AG) relates to oxo-substitutedimidazo[1,2-b]pyridazines as kinase inhibitors, particularly PKC(protein kinase C) inhibitors, in particular PKC theta inhibitors.

WO 2008/025822 A1 (Cellzome (UK) Ltd.) relates to diazolodiazinederivatives as kinase inhibitors. In particular, WO 2008/025822 A1relates inter alia to imidazo[1,2-b]pyridazines as kinase inhibitors,particularly inducible T cell kinase (abbreviated to “Itk”) inhibitors.

WO 2008/030579 A2 (Biogen Idec MA Inc.) relates to modulators ofinterleukin-1 (IL-1) receptor-associated kinase (abbreviated to “IRAK”).In particular, WO 2008/030579 A2 relates inter alia toimidazo[1,2-b]pyridazines.

WO 2008/058126 A2 (Supergen, Inc.) relates inter alia toimidazo[1,2-b]pyridazine derivatives as protein kinase inhibitors,particularly PIM kinase inhibitors.

WO 2009/060197 A1 (Centro Nacional de Investigaciones Oncologicas(CNIO)) relates to imidazopyridazines as protein kinase inhibitors, suchas the PIM family kinases.

U.S. Pat. No. 4,408,047 (Merck & Co., Inc.,) relates inter alia toimidazopyridazines having a 3-amino-2-OR-propoxy substituent havingbeta-adrenergic blocking activity.

WO 03/018020 A1 (Takeda Chemical Industries, Ltd.) relates to inhibitorsagainst c-Jun N-terminal kinase, containing compounds which are, interalia, imidazo[1,2-b]-pyridazines.

WO 2008/052734 A1 (Novartis AG) relates to heterocyclic compounds asantiinflammatory agents. In particular said compounds are, inter alia,imidazo[1,2-b]pyridazines. The compounds are useful for treatingdiseases mediated by the ALK-5 and/or ALK-4 receptor, and are alsouseful for treating diseases mediated by the PI3K receptor, the JAK-2receptor and the TRK receptor.

WO 2008/072682 A1 (Daiichi Sankyo Company, Limited) relate toimidazo[1,2-b]pyridazine derivative which has an action of inhibitingTNF-alpha production, exerts an effect in a pathological model ofinflammatory disease and/or auto-immune disease.

WO 2008/079880 A1 (Alcon Research, Ltd.) relates to6-aminoimidazo[1,2-b]pyridazine analogues as Rho-kinase inhibitors forthe treatment of glaucoma and ocular hypertension.

WO 2009/091374 A2 (Amgen Inc.) relates to fused heterocyclicderiviatives. Selected compounds are effective for prophylaxis andtreatment of diseases, such as hepatocyte growth factor (“HGF”)diseases.

In J. Med. Chem., 2005, 48, 7604-7614, is an article entitled“Structural Basis of Inhibitor Specificity of the Protooncogene ProviralInsertion Site in Moloney Murine Leukemia Virus (PIM-1) Kinase”, anddiscloses, inter alia, imidazo[1,2-b]pyridazines as inhibitor structuresused in the study described therein.

In J. Med. Chem., 2010, 53, 6618-6628, is an article entitled “Discoveryof Mitogen-Activated Protein Kinase-Interacting Kinase 1 Inhibitors by aComprehensive Fragment-Oriented Virtual Screening Approach”, anddiscloses, inter alia, in Table 1., some specificimidazo[1,2-b]pyridazines as compounds identified as MKNK-1 inhibitors.

In Cancer Res Mar. 1, 2011, 71, 1849-1857 is an article entitled“Therapeutic inhibition of MAP kinase interacting kinase blockseukaryotic initiation factor 4E phosphorylation and suppresses outgrowthof experimental lung mestastases”, and discloses, inter alia, that theknown antigfungal agent Cercosporamide is an inhibitor of MKNK1.

However, the state of the art described above does not describe thespecific substituted imidazopyridazine compounds of general formula (I)of the present invention as defined herein, i.e. animidazo[1,2-b]pyridazinyl moiety, bearing:

-   -   in its 3-position, a:

-   -   in its 6-position, a group of structure:

wherein:

-   -   * indicates the point of attachment of said group with the rest        of the molecule,    -   R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or        a C₃-C₆-cycloalkyl- group which is optionally substituted as        defined herein, and    -   R2 represents a substituent as defined herein;        or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,        or a salt thereof, or a mixture of same, as described and        defined herein, and as hereinafter referred to as “compounds of        the present invention”, or their pharmacological activity.

It has now been found, and this constitutes the basis of the presentinvention, that said compounds of the present invention have surprisingand advantageous properties.

In particular, said compounds of the present invention have surprisinglybeen found to effectively inhibit MKNK-1 kinase and may therefore beused for the treatment or prophylaxis of diseases of uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses or diseaseswhich are accompanied with uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses is mediated by MKNK-1 kinase, such as, for example,haematological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 6-membered heterocycloalkylwhich is connected as Spiro; aryl- optionally substituted one or moretimes, independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent;heteroaryl-optionally substituted one or more times, independently fromeach other, with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′,—C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′,—N(R′)C(═O)R′, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group;R2 represents a hydrogen atom;R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂,—NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,—N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,—N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, C₃-C₆-cycloalkoxy-,C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-, —OC(═O)R′, —SH, C₁-C₆-alkyl-S—,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″ group;R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-memberedheterocycloalkyl-, aryl- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;n represents an integer of 0, 1, 2 or 3;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In accordance with an embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-; aryl- optionally substituted one ormore times, independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group;R2 represents a hydrogen atom;R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂,—NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,—N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,—N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —SH, C₁-C₆-alkyl-S—,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″ group;R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-memberedheterocycloalkyl-, aryl- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;n represents an integer of 0, 1, 2 or 3;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom”, “halo-” or “Hal-” is to be understood asmeaning a fluorine, chlorine, bromine or iodine atom, preferably afluorine, chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group having 1, 2,3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl,hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or anisomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms(“C₁-C₄-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl,iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3carbon atoms (“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl- oriso-propyl group.

The term “halo-C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group in which theterm “C₁-C₆-alkyl” is defined supra, and in which one or more hydrogenatoms is replaced by a halogen atom, in identically or differently, i.e.one halogen atom being independent from another. Particularly, saidhalogen atom is F. Said halo-C₁-C₆-alkyl group is, for example, —CF₃,—CHF₂, —CH₂F, —CF₂CF₃, or —CH₂CF₃.

The term “C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent, hydrocarbon group of formula—O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy,sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomerthereof. Particularly, said “C₁-C₆-alkoxy” can contain 1, 2, or 3 carbonatoms, (a “C₁-C₃-alkoxy”).

The term “halo-C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent C₁-C₆-alkoxy group, as definedsupra, in which one or more of the hydrogen atoms is replaced, inidentically or differently, by a halogen atom. Particularly, saidhalogen atom is F. Said halo-C₁-C₆-alkoxy group is, for example, —OCF₃,—OCHF₂, —OCH₂F, —OCF₂CF₃, or —OCH₂CF₃.

The term “C₁-C₆-alkoxy-C₁-C₆-alkyl” is to be understood as preferablymeaning a linear or branched, saturated, monovalent alkyl group, asdefined supra, in which one or more of the hydrogen atoms is replaced,in identically or differently, by a C₁-C₆-alkoxy group, as definedsupra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl,butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl,pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, in which theterm “C₁-C₆-alkyl” is defined supra, or an isomer thereof.

The term “halo-C₁-C₆-alkoxy-C₁-C₆-alkyl” is to be understood aspreferably meaning a linear or branched, saturated, monovalentC₁-C₆-alkoxy-C₁-C₆-alkyl group, as defined supra, in which one or moreof the hydrogen atoms is replaced, in identically or differently, by ahalogen atom. Particularly, said halogen atom is F. Saidhalo-C₁-C₆-alkoxy-C₁-C₆-alkyl group is, for example, —CH₂CH₂OCF₃,—CH₂CH₂OCHF₂, —CH₂CH₂OCH₂F, —CH₂CH₂OCF₂CF₃, or —CH₂CH₂OCH₂CF₃.

The term “C₂-C₆-alkenyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains one ormore double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkenyl”), it being understoodthat in the case in which said alkenyl group contains more than onedouble bond, then said double bonds may be isolated from, or conjugatedwith, each other. Said alkenyl group is, for example, a vinyl, allyl,(E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl,(Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl,(E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl,(E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl,(Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl,(Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl,2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl,(E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl,2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl,(E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl,(Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl,(E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl,(Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl,1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl,3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl,4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl,(E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl,(E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl,(E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,(E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl,(E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl,(E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl,(E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl,(E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl,(E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl,(E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl,2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl,(Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,(E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl,(Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl,(Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl,2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl,(Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl,(Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl,(Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl,buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienylgroup. Particularly, said group is vinyl or allyl.

The term “C₂-C₆-alkynyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group which contains one ormore triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkynyl”). Said C₂-C₆-alkynylgroup is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl,pent-4-ynyl, hex-1-ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl,1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl,1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl,3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl,2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl,1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl,2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl,1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl,1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or3,3-dimethylbut-1-ynyl group. Particularly, said alkynyl group isethynyl, prop-1-ynyl, or prop-2-inyl.

The term “C₃-C₁₀-cycloalkyl” is to be understood as meaning a saturated,monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5,6, 7, 8, 9 or 10 carbon atoms (“C₃-C₁₀-cycloalkyl”). SaidC₃-C₁₀-cycloalkyl group is for example, a monocyclic hydrocarbon ring,e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring,e.g. a perhydropentalenylene or decalin ring. Particularly, said ringcontains 3, 4, 5 or 6 carbon atoms (“C₃-C₆-cycloalkyl”).

The term “C₃-C₆-cycloalkoxy” is to be understood as preferably meaning asaturated, monovalent, hydrocarbon ring which contains 3, 4, 5 or 6carbon atoms of formula —O-cycloalkyl, in which the term “cycloalkyl” isdefined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy orcyclohexyloxy.

The term “C₃-C₆-cycloalkyl-C₁-C₃-alkoxy” is to be understood aspreferably meaning a saturated, monovalent alkoxy group, as definedsupra, in which one of the hydrogen atoms is replaced by aC₃-C₆-cycloalkyl group, as defined supra, e.g. cyclopropylalkoxy,cyclobutylalkoxy, cyclopentylalkoxy, cyclohexylalkoxy group, in whichthe term “alkoxy” is defined supra, or an isomer thereof.

The term “C₄-C₁₀-cycloalkenyl” is to be understood as preferably meaninga monovalent, mono-, or bicyclic hydrocarbon ring which contains 4, 5,6, 7, 8, 9 or 10 carbon atoms and one, two, three or four double bonds,in conjugation or not, as the size of said cycloalkenyl ring allows.Said C₄-C₁₀-cycloalkenyl group is for example, a monocyclic hydrocarbonring, e.g. a cyclobutenyl, cyclopentenyl, or cyclohexenyl or a bicyclichydrocarbon, e.g.:

The term “3- to 10-membered heterocycloalkyl”, is to be understood asmeaning a saturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or moreheteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O)₂,NR^(a), in which R^(a) represents a hydrogen atom, or a C₁-C₆-alkyl- orhalo-C₁-C₆-alkyl- group; it being possible for said heterocycloalkylgroup to be attached to the rest of the molecule via any one of thecarbon atoms or, if present, the nitrogen atom.

Particularly, said 3- to 10-membered heterocycloalkyl can contain 2, 3,4, or 5 carbon atoms, and one or more of the above-mentionedheteroatom-containing groups (a “3- to 6-membered heterocycloalkyl”),more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms,and one or more of the above-mentioned heteroatom-containing groups (a“5- to 6-membered heterocycloalkyl”).

Particularly, without being limited thereto, said heterocycloalkyl canbe a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-memberedring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such astetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanylring, for example. Optionally, said heterocycloalkyl can be benzo fused.

Said heterocyclyl can be bicyclic, such as, without being limitedthereto, a 5,5-membered ring, e.g. ahexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclicring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring.

As mentioned supra, said nitrogen atom-containing ring can be partiallyunsaturated, i.e. it can contain one or more double bonds, such as,without being limited thereto, a 2,5-dihydro-1H-pyrrolyl,4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl ring,for example, or, it may be benzo-fused, such as, without being limitedthereto, a dihydroisoquinolinyl ring, for example.

The term “4- to 10-membered heterocycloalkenyl”, is to be understood asmeaning an unsaturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or moreheteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O)₂,NR^(a), in which R^(a) represents a hydrogen atom, or a C₁-C₆-alkyl- orhalo-C₁-C₆-alkyl- group; it being possible for said heterocycloalkenylgroup to be attached to the rest of the molecule via any one of thecarbon atoms or, if present, the nitrogen atom. Examples of saidheterocycloalkenyl may contain one or more double bonds, e.g.4H-pyranyl, 2H-pyranyl, 3H-diazirinyl, 2,5-dihydro-1H-pyrrolyl,[1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl,2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl,4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl group, or, it may be benzofused.

The term “aryl” is to be understood as preferably meaning a monovalent,aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbonring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a“C₆-C₁₄-aryl” group), particularly a ring having 6 carbon atoms (a“C₆-aryl” group), e.g. a phenyl group; or a biphenyl group, or a ringhaving 9 carbon atoms (a “C₉-aryl” group), e.g. an indanyl or indenylgroup, or a ring having 10 carbon atoms (a “C₁₀-aryl” group), e.g. atetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13carbon atoms, (a “C₁₃-aryl” group), e.g. a fluorenyl group, or a ringhaving 14 carbon atoms, (a “C₁₄-aryl” group), e.g. an anthranyl group.

The term “heteroaryl” is understood as preferably meaning a monovalent,monocyclic-, bicyclic- or tricyclic aromatic ring system having 5, 6, 7,8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl”group), particularly 5 or 6 or 9 or 10 atoms, and which contains atleast one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur, and in addition ineach case can be benzocondensed. Particularly, heteroaryl is selectedfrom thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof,such as, for example, benzofuranyl, benzothienyl, benzoxazolyl,benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl,isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, etc., and benzo derivatives thereof, such as, for example,quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl,purinyl, etc., and benzo derivatives thereof; or cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,xanthenyl, or oxepinyl, etc.

In general, and unless otherwise mentioned, the heteroarylic orheteroarylenic radicals include all the possible isomeric forms thereof,e.g. the positional isomers thereof. Thus, for some illustrativenon-restricting example, the term pyridinyl or pyridinylene includespyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene,pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienyleneincludes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl”, “C₁-C₆-haloalkyl”, “C₁-C₆-alkoxy”, or“C₁-C₆-haloalkoxy” is to be understood as meaning an alkyl group havinga finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6carbon atoms. It is to be understood further that said term “C₁-C₆” isto be interpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₅,C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅; particularly C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₅, C₁-C₆; more particularly C₁-C₄; in the case of “C₁-C₆-haloalkyl”or “C₁-C₆-haloalkoxy” even more particularly C₁-C₂.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext, e.g. in the context of the definitions of “C₂-C₆-alkenyl” and“C₂-C₆-alkynyl”, is to be understood as meaning an alkenyl group or analkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2,3, 4, 5, or 6 carbon atoms. It is to be understood further that saidterm “C₂-C₆” is to be interpreted as any sub-range comprised therein,e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄, C₂-C₅; particularly C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or five,particularly one, two, three or four, more particularly one, two orthree, even more particularly one or two”.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S,³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention may contain one or more asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric centre, and diastereomeric mixtures in the case ofmultiple asymmetric centres. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

The compounds of the present invention may contain sulphur atoms whichare asymmetric, such as an asymmetric sulphoxide or sulphoximine group,of structure:

for example,in which * indicates atoms to which the rest of the molecule can bebound.

Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDaicel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. R- or S-isomers, or E- or Z-isomers,in any ratio. Isolation of a single stereoisomer, e.g. a singleenantiomer or a single diastereomer, of a compound of the presentinvention may be achieved by any suitable state of the art method, suchas chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers.For example, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, or a triazole moiety for example can exist as a 1H tautomer,a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said1H, 2H and 4H tautomers, namely:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, such as hydrochloric,hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitricacid, for example, or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present inventioncontaining a hydroxy group includes inorganic esters such as phosphateesters and [alpha]-acyloxyalkyl ethers and related compounds which as aresult of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

In accordance with a second embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 6-membered heterocycloalkylwhich is connected as spiro; aryl- optionally substituted one or moretimes, independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent;heteroaryl-optionally substituted one or more times, independently fromeach other, with an

R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group;

R2 represents a hydrogen atom;R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂,—NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,—N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,—N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, C₃-C₆-cycloalkoxy-,C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-, —OC(═O)R′, —SH, C₁-C₆-alkyl-S—,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″ group;R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl- group;R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R¹)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from: C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;n represents an integer of 0, 1, 2 or 3;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In accordance with a variant of the second embodiment of the firstaspect, the present invention covers compounds of general formula (I),supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-; aryl- optionally substituted one ormore times, independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group;R2 represents a hydrogen atom;R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂,—NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,—N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,—N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —SH, C₁-C₆-alkyl-S—,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″ group;R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl- group;R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R¹)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;n represents an integer of 0, 1, 2 or 3;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In accordance with a third embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 6-membered heterocycloalkylwhich is connected as Spiro; aryl- optionally substituted one or moretimes, independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent;heteroaryl-optionally substituted one or more times, independently fromeach other, with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′,—C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′,—N(R′)C(═O)R′, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group;R2 represents a hydrogen atom;R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —NHR′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, C₃-C₆-cycloalkoxy-,C₃-C₆-cycloalkyl-C₁-C₃-alkoxy- group;R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl- group;R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;n represents an integer of 0 or 1;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In accordance with a variant of the third embodiment of the firstaspect, the present invention covers compounds of general formula (I),supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-; aryl- optionally substituted one ormore times, independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group;R2 represents a hydrogen atom;R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy- group;R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl- group;R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;n represents an integer of 0 or 1;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In accordance with a fourth embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₃-alkyl-, C₁-C₃-haloalkyl-,C₃-C₆-cycloalkyl-, 3- to 6-membered heterocycloalkyl which is connectedas Spiro; aryl- optionally substituted one or two times, independentlyfrom each other, with an R substituent; aryl-C₁-C₆-alkyloxy- optionallysubstituted one or more times, independently from each other, with an Rsubstituent; heteroaryl- optionally substituted one or two times,independently from each other, with an R substituent; —C(═O)NH₂, —NH₂,—NHR′, —N(R′)R″, —OH, C₁-C₃-alkoxy-, C₁-C₃-haloalkoxy-;R2 represents a hydrogen atom;R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —NHR′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, C₃-C₆-cycloalkoxy-,C₃-C₆-cycloalkyl-C₁-C₃-alkoxy- group;R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl- group;R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;n represents an integer of 0 or 1;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In accordance with a variant of the fourth embodiment of the firstaspect, the present invention covers compounds of general formula (I),supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₃-alkyl-, C₁-C₃-haloalkyl-,C₃-C₆-cycloalkyl-; aryl-optionally substituted one or two times,independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or two times, independently from each other,with an R substituent; —C(═O)NH₂, —NH₂, —NHR′, —N(R′)R″, —OH,C₁-C₃-alkoxy-, C₁-C₃-haloalkoxy-;R2 represents a hydrogen atom;R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy- group;R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl- group;R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-;n represents an integer of 0 or 1;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In accordance with a fifth embodiment of the first aspect, the presentinvention covers compounds of general formula (I), supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group, which is optionally substituted with one or moresubstituents selected, independently from each other, from:a 3- to 6-membered heterocycloalkyl which is connected as Spiro; aryl-optionally substituted one or two times, independently from each other,with an R substituent; aryl-C₁-C₆-alkyloxy- optionally substituted oneor more times, independently from each other, with an R substituent;R2 represents a hydrogen atom;R3 represents a substituent selected from:a C₁-C₆-alkoxy-, C₃-C₆-cycloalkoxy-, C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-,—NHR′, —OH group,R4 represents a hydrogen atom;n represents an integer of 0 or 1;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In accordance with a variant of the fifth embodiment of the firstaspect, the present invention covers compounds of general formula (I),supra, in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule;R1 represents a linear C₂-C₆-alkyl- group, which is optionallysubstituted with one or more substituents selected, independently fromeach other, from:aryl- optionally substituted one or two times, independently from eachother, with an R substituent; aryl-C₁-C₆-alkyloxy- optionallysubstituted one or more times, independently from each other, with an Rsubstituent;R2 represents a hydrogen atom;R3 represents a substituent selected from:a C₁-C₆-alkoxy- group;R4 represents a hydrogen atom;n represents an integer of 0 or 1;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 6-membered heterocycloalkylwhich is connected as spiro; aryl- optionally substituted one or moretimes, independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent;heteroaryl-optionally substituted one or more times, independently fromeach other, with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′,—C(═O)N(R′)R″, —C(═O)OH, —C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′,—N(R′)C(═O)R′, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-,

C₃-C₁₀-cycloalkyl-; aryl- optionally substituted one or more times,independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R2 represents a hydrogen atom.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂,—NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,—N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,—N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, C₃-C₆-cycloalkoxy-,C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-, —OC(═O)R′, —SH, C₁-C₆-alkyl-S—,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″ group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂,—NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂,—N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′,—N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′,—N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —SH, C₁-C₆-alkyl-S—,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″ group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-memberedheterocycloalkyl-, aryl- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′,—OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S—, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R′ and R″ represent, independently from each other, a substituentselected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

n represents an integer of 0, 1, 2 or 3.R4 represents a substituent selected from:a hydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl- group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, C₃-C₆-cycloalkoxy-,C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-, —NHR′— group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy- group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

n represents an integer of 0 or 1.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₃-alkyl-, C₁-C₃-haloalkyl-,C₃-C₆-cycloalkyl-, 3- to 6-membered heterocycloalkyl which is connectedas spiro; aryl- optionally substituted one or two times, independentlyfrom each other, with an R substituent; aryl-C₁-C₆-alkyloxy- optionallysubstituted one or more times, independently from each other, with an Rsubstituent; heteroaryl- optionally substituted one or two times,independently from each other, with an R substituent; —C(═O)NH₂, —NH₂,—NHR′, —N(R′)R″, —OH, C₁-C₃-alkoxy-, C₁-C₃-haloalkoxy-.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group which is optionally substituted with one or moresubstituents selected, independently from each other, from:a halogen atom, a —CN, C₁-C₃-alkyl-, C₁-C₃-haloalkyl-,C₃-C₆-cycloalkyl-; aryl-optionally substituted one or two times,independently from each other, with an R substituent;aryl-C₁-C₆-alkyloxy- optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or two times, independently from each other,with an R substituent; —C(═O)NH₂, —NH₂, —NHR′, —N(R′)R″, —OH,C₁-C₃-alkoxy-, C₁-C₃-haloalkoxy-.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R1 represents a linear C₂-C₆-alkyl-, a branched C₃-C₆-alkyl-, or aC₃-C₆-cycloalkyl group, which is optionally substituted with one or moresubstituents selected, independently from each other, from:3- to 6-membered heterocycloalkyl which is connected as Spiro, aryl-optionally substituted one or two times, independently from each other,with an R substituent; aryl-C₁-C₆-alkyloxy- optionally substituted oneor more times, independently from each other, with an R substituent.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R1 represents a linear C₂-C₆-alkyl- group, which is optionallysubstituted with one or more substituents selected, independently fromeach other, from:aryl- optionally substituted one or two times, independently from eachother, with an R substituent; aryl-C₁-C₆-alkyloxy- optionallysubstituted one or more times, independently from each other, with an Rsubstituent.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a C₁-C₆-alkoxy-, C₃-C₆-cycloalkoxy-, C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-,OH—, —NHR′— group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a C₃-C₆-cycloalkoxy-, group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a C₃-C₆-cycloalkyl-C₁-C₃-alkoxy group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a OH— group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a —NHR′— group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R3 represents a substituent selected from:a C₁-C₆-alkoxy- group.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

R4 represents a hydrogen atom.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

n represents an integer of 0.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), wherein:

n represents an integer of 1.

In a further embodiment of the above-mentioned aspect, the inventionrelates to compounds of formula (I), according to any of theabove-mentioned embodiments, in the form of or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of same.

It is to be understood that the present invention relates to anysub-combination within any embodiment or aspect of the present inventionof compounds of general formula (I), supra.

More particularly still, the present invention covers compounds ofgeneral formula (I) which are disclosed in the Example section of thistext, infra.

In accordance with another aspect, the present invention covers methodsof preparing compounds of the present invention, said methods comprisingthe steps as described in the Experimental Section herein.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I), particularly in themethod described herein. In particular, the present invention coverscompounds of general formula (V):

in which A, R2, R3, R4 and n are as defined for the compound of generalformula (I) supra, and X represents a leaving group, such as a halogenatom, for example a chlorine, bromine or iodine atom, or aperfluoroalkylsulfonate group for example, such as atrifluoromethylsulfonate group or a nonafluorobutylsulfonate group, forexample.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula (V):

in which A, R2, R3, R4 and n are as defined for the compound of generalformula (I) supra, and X represents a leaving group, such as a halogenatom, for example a chlorine, bromine or iodine atom, or aperfluoroalkylsulfonate group for example, such as atrifluoromethylsulfonate group for example, for the preparation of acompound of general formula (I) as defined supra.

Experimental Section

The following table lists the abbreviations used in this paragraph, andin the examples section.

Abbreviation Meaning DMSO dimethyl sulfoxide THF tetrahydrofurane NMRnuclear magnetic resonance DMF N,N-dimethylforamide TFA trifluoroaceticacid MS mass spectroscopy R_(t) retention time HPLC, LC high performanceliquid chromatography h hour min minute PdCl₂(PPh₃)₂dichlorobis(triphenylphosphine)palladium(II)

Syntheses of Compounds (Overview):

The compounds of the present invention can be prepared as described inthe following section. Scheme 1 and the procedures described belowillustrate general synthetic routes to the compounds of general formula(I) of the invention and are not intended to be limiting. It is clear tothe person skilled in the art that the order of transformations asexemplified in Scheme 1 can be modified in various ways. The order oftransformations exemplified in the Scheme 1 is therefore not intended tobe limiting. In addition, interconversion of any of the substituents,R1, R2, R3, R4 and A, can be achieved before and/or after theexemplified transformations.

These modifications can be such as the introduction of protectinggroups, cleavage of protecting groups, exchange, reduction or oxidationof functional groups, halogenation, metallation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3^(rd) edition, Wiley 1999). Specific examples aredescribed in the subsequent paragraphs. Further, it is possible that twoor more successive steps may be performed without work-up beingperformed between said steps, e.g. a “one-pot” reaction, as iswell-known to the person skilled in the art.

in which A, R1, R2, R3, R4 and n are as defined supra, and X and Yrepresent a leaving group, such as a halogen atom, for example achlorine, bromine or iodine atom, or a perfluoroalkylsulfonate group forexample, such as a trifluoromethylsulfonate group, anonafluorobutylsulfonate group, for example.

In the first step, a compound of formula A, i.e. a dichloropyridazinebearing suitable X substituents, can be reacted with ammonia at elevatedtemperature and pressure to give a compound of general formula B. [inanalogy to W0200733080, which is hereby incorporated herein in itsentirety as reference]

In the second step, a compound of general formula B reacts, for example,with chloroacetaldehyde or bromoacetaldehyde diacetal to give thebicyclic ring system C [in analogy to DE102006029447, which is herebyincorporated herein in its entirety as reference].

Activation of position 3 of the bicyclic system to give compounds ofgeneral formula D can be accomplished, for example, by bromination oriodination of compounds of general formula C using N-bromo-succinimideor N-iodo-succinimide, respectively.

In the fourth step, introduction of residue A-[R3]_(n) can be achievedusing suitably catalyzed cross-coupling reactions employing, forexample, boronic acids or stannanes, which results in compounds ofgeneral formula E.

Compounds of general formula E serve as central intermediates for theintroduction of various side chains containing an alcohol function,which results in imidazopyridazinyl-ethers of general formula (I).Introduction of the side chains can be achieved, for example, byemploying bases such as sodium hydride. Depending on the nature of theside chain it may be necessary to run these reactions at elevatedtemperatures. It may also be necessary to introduce side chainsdecorated with suitable protecting groups on functional groups which maydisturb the desired reaction.

The fourth and the fifth step of the described sequence may also beinterconverted as illustrated in Scheme 2.

In accordance with an embodiment, the present invention also relates toa method of preparing a compound of general formula (I) supra, saidmethod comprising the step of allowing an intermediate compound ofgeneral formula (V):

in which A, R2, R3, R4 and n are as defined for the compound of generalformula (I) supra, and X represents a leaving group, such as a halogenatom, for example a chlorine, bromine or iodine atom, or aperfluoroalkylsulfonate group for example, such as atrifluoromethylsulfonate group or a nonafluorobutylsulfonate group, forexample,to react with a compound of general formula (III):

in which R1 is defined for the compound of general formula (I), supra,thereby giving a compound of general formula (I):

in which A, R1, R2, R3, R4 and n are as defined for the compound ofgeneral formula (I) supra.

General Part

Chemical names were generated using ACD/Name Batch Version 12.01.

HPLC Methods: Method 1:

Instrument: Waters Acquity UPLCMS ZQ4000; Column: Acquity UPLC BEH C181.7 μm, 50×2.1 mm; eluent A: water+0.05 vol % formic acid, Eluent B:acetonitrile+0.05 vol % formic acid gradient: 0-1.6 min 1-99% B, 1.6-2.0min 99% B; flow 0.8 mL/min; temperature: 60° C.; injection: 2 μL; DADscan: 210-400 nm; ELSD

Method 2:

Instrument: Waters Acquity UPLCMS SQD 3001; Column: Acquity UPLC BEH C181.7 μm, 50×2.1 mm; eluent A: water+0.1 vol % formic acid (95%), eluentB: acetonitrile, gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow0.8 mL/min; temperature: 60° C.; injection: 2 μL; DAD scan: 210-400 nm;ELSD

Method 3:

Instrument: Waters Acquity UPLCMS SQD; Column: Acquity UPLC BEH C18 1.7μm, 50×2.1 mm; eluent A: water+0.05 vol % formic acid (95%), eluent B:acetonitrile+0.05 vol % formic acid (95%), gradient: 0-1.6 min 1-99% B,1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60° C.; injection: 2μL; DAD scan: 210-400 nm; ELSD

Method 4:

Instrument: Waters Acquity UPLC-MS SQD; Column: Acquity UPLC BEH C18 1.750×2.1 mm; eluent A: water+0.1 vol % formic acid (99%), eluent B:acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8mL/min; temperature: 60° C.; injection: 2 μL; DAD scan: 210-400 nm;ELSD.

Method 5:

Instrument: Waters Acquity UPLCMS SQD 3001; Column: Acquity UPLC BEH C181.7 μm, 50×2.1 mm; eluent A: water+0.2 vol. % ammonia (32%), eluent B:acetonitrile, gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8mL/min; temperature: 60° C.; injection: 2 μL; DAD scan: 210-400 nm; ELSD

INTERMEDIATES Intermediate 1 3-Bromo-6-chloro-imidazo[1,2-b]pyridazine

3-Bromo-6-chloro-imidazo[1,2-b]pyridazine was synthesised as describedfor example in WO 2007/147646 or DE 10 2006 029447, e.g. as follows:

Step 1: Preparation of 6-Chloroimidazo[1,2-b]pyridazine

5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated togetherwith 4.7 mL (40 mmol) of chloroacetaldehyde (55% strength in water) in15 mL of n-butanol at 120° C. for a period of 5 days. After the reactionwas complete, the reaction mixture was added to saturated sodiumbicarbonate solution and extracted three times with ethyl acetate. Thecombined organic phases were then washed with sat. sodium chloridesolution and dried over sodium sulfate, and the solvent was removed invacuo. In the final purification by chromatography on silica gel, 4.17 g(70%) of the desired product were isolated in the form of an amorphouswhite solid.

¹H-NMR (CHLOROFORM-d): δ [ppm]=7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d,1H); 7.96 (d, 1H).

Step 2: Preparation of 3-Bromo-6-chloroimidazo[1,2-b]pyridazine

478 mg (3.11 mmol) of 6-chloroimidazo[1,2-b]pyridazine were introducedinto 10 mL of chloroform under argon and, while cooling in ice, 664 mg(3.73 mmol) of N-bromosuccuinimide were added. After the addition wascomplete, the reaction mixture was stirred at room temperatureovernight. The reaction mixture was then mixed with water and ethylacetate and, after addition of saturated sodium bicarbonate solution,the phases were separated. The aqueous phase was extracted three moretimes with ethyl acetate. The combined organic phases were then washedwith saturated sodium chloride solution and dried over sodium sulfate.In the final removal of the solvent in vacuo, the desired product wasisolated in quantitative yield in the form of an amorphous white solidwhich was employed without further chromatographic purification insubsequent reactions.

¹H-NMR (CHLOROFORM-d): δ [ppm]=7.12 (d, 1H); 7.79 (s, 1H); 7.90, (d,1H).

Intermediate 26-Chloro-3-(furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine

A mixture of 2.0 g (16.8 mmol) furo[3,2-b]-pyridine anhydrous THF (100mL) was cooled to −78° C. 10.1 mL (25.2 mmol) of a 1.6 M solution ofn-butyllithium in hexane was added and the resulting mixture stirred for1 h at −78° C. 6.8 mL (25.2 mmol) of tributyltin chloride was added at−78° C. The cooling bath was removed and the reaction was stirred atroom temperature over night.

Methanol was carefully added and the solvent evaporated. The obtainedresidue was purified by flash chromatography to yield 7.4 g of crudeproduct of the corresponding 2-stannylbenzofurane, which was usedwithout further purification.

In an inert atmosphere, 3.0 g (12.9 mmol) of3-bromo-6-chloro-imidazo[1,2-b]pyridazine, 6.85 g (16.8 mmol) of thecrude 2-stannylfuro[3,2-b]pyridine, 246 mg (1.29 mmol) copper (I) iodideand 453 mg (0.645 mmol) bis(triphenylphosphine) palladium(II)chloride in100 mL of THF was stirred over night at 85° C. in a sealed pressuretube. The solvent was evaporated, the obtained solid was digested indichloromethane/methanol and filtered off. The solid was washed withmethanol and hexane to give 2 g of the title compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=7.35-7.45 (1H), 7.57-7.64 (1H),7.65-7.70 (1H), 8.08-8.15 (1H), 8.40-8.47 (1H), 8.47-8.52 (1H),8.54-8.62 (1H).

LCMS (Method 3): R_(t)=0.91 min; MS (ESIpos) m/z=271 [M+H]⁺.

Intermediate 36-Chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine

6-Chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine wasprepared in analogy to6-chloro-3-(furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine startingfrom 314 mg (1.35 mmol) of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine toyield 62% of a solid material.

LCMS (Method 2): R_(t)=0.60 min; MS (ESIpos) m/z=271 [M+H]⁺.

Intermediate 46-Chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine

6-Chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewas prepared in analogy to6-chloro-3-(furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine startingfrom 2.4 g (10.3 mmol) of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine toyield 2.64 g of a solid material which was used as crude product.

LCMS (Method 3): R_(t)=1.24 min; MS (ESIpos) m/z=301 [M+H]⁺.

Intermediate 56-Chloro-3-(furo[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine

A mixture of furo[2,3-c]-pyridine (918 mg, 7.7 mmol) in anhydrous THF(45 mL) was cooled to −78° C. A solution of n-butyllithium in hexane(4.6 ml, c=2.5 M, 11.6 mmol) was added and the resulting mixture wasstirred for 1 h at −78° C. Tributyltin chloride (3.1 mL, 11.6 mmol) wasadded at −78° C. The cooling bath was removed and the reaction mixturewas stirred at room temperature for 2 h.

Methanol was added and the solvent was evaporated. Aminophase-silica-gelchromatography gave 1.9 g of crude2-(tributylstannyl)furo[2,3-c]pyridine which was used without furtherpurification.

To a stirred solution of crude 2-(tributylstannyl)furo[2,3-c]pyridine(1.9 g) in THF (20 mL) in an inert atmosphere was added3-bromo-6-chloro-imidazo[1,2-b]pyridazine (676 mg, 2.9 mmol), copper (I)iodide (55 mg, 0.29 mmol) bis(triphenylphosphine) palladium(II)chloride(102 mg, 0.145 mmol) and triphenylphosphine (38 mg, 0.145 mmol). Themixture was heated to reflux for 2 h. The solvent was removed in vacuum.The residue was dissolved in a mixture of dichloromethane and methanol,filtered through an aminophase-silica-gel column and the solvent wasremoved in vacuum. Silicagel chromatography gave a solid that wastriturated with a mixture of ethyl acetate and hexane to give 343 mg ofthe title compound, which was used without further purification.

¹H-NMR (300 MHz, CHLOROFORM-d): δ [ppm]=7.24 (d, 1H), 7.62 (d, 1H), 7.71(s, 1H), 8.07 (d, 1H), 8.43 (s, 1H), 8.48 (d, 1H), 8.95 (s, 1H).

LCMS (Method 3): Rt=0.63 min; MS (ESIpos) m/z=271 [M+H]⁺.

Intermediate 66-Chloro-3-[4-(propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazine

Step 1: At 0° C., 3.1 g (78 mmol) sodium hydride (60% suspension inmineral oil) was carefully added to 4.7 g (78 mmol) isopropanol in 100mL of anhydrous THF. The mixture was stirred at 0° C. for 15 min. 3 g(19.5 mmol) 4-chlorofuro[3,2-c]pyridine was added. The mixture wasstirred at 80° C. for 20 h.

Water was carefully added. The volume of the resulting suspension wasreduced by evaporation. Water was added. The aqueous layer was extractedconsecutively with ethyl acetate. The combined organic layers werewashed with brine, dried over sodium sulfate and evaporated to give 4.6g of a crude product, which was used without further purification instep 2.

Step 2: 3.5 g (19.5 mmol) of the crude product from step 1 in 44 mLanhydrous THF was cooled to −78° C. 11.7 mL (29 mmol) of a 2.5 Msolution of n-butyl lithium in hexane was added. The mixture was stirredfor 90 min at −78° C. 6.8 mL (29 mmol) of triisopropyl borate was addedat −78° C. The cooling bath was removed and the mixture was stirred atroom temperature for 1 h.

A small amount of water was added and the solvent was evaporated to 7.7g of a crude product which was used without further purification in step3.

Step 3: To 1.9 g (8 mmol) 3-bromo-6-chloroimidazo[1,2-b]pyridazine in 68mL dioxane were added 1.9 g (8.4 mmol) of the crude product from step 2,370 mg (0.32 mmol) tetrakis(triphenylphosphin)palladium(0) and 12 mL ofa 2 M aqueous solution of sodium carbonate. The mixture was stirred at100° C. for 18 h.

The reaction mixture was poured into saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, and concentrated. The obtainedsolid material was digestend with a 9:1 mixture of dichloromethane andmethanol, filtered off, washed with dichloromathene and dried in vacuoto give 428 mg of the title compound as solid material. The motherliquor was concentrated and subjected to flash chromatography to giveanother fraction of product containing material, which was againdigested in methanol and dichlormethane to give another 316 mg of thetitle compound.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.38 (6H), 5.47 (1H), 7.33 (1H), 7.44(1H), 7.53 (1H), 8.03 (1H), 8.36-8.40 (2H).

LCMS (Method 3): R_(t)=1.43 min; MS (ESIpos) m/z=329 [M+H]⁺.

Intermediate 76-Chloro-3-[4-(2,2-dimethylpropoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]-pyridazine

6-Chloro-3-[4-(2,2-dimethylpropoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]-pyridazinewas prepared in analogy to6-chloro-3-[4-(propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazinestarting from 2.8 g (12.2 mmol) of3-bromo-6-chloro-imidazo[1,2-b]pyridazine to yield 1.3 g of the titlecompound after digestion in a 9:1 mixture of dichloromethane andmethanol.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.03 (9H), 4.15 (2H), 7.35 (1H), 7.47(1H), 7.53 (1H), 8.01 (1H), 8.37 (1H).

LCMS (Method 3): Rt=1.59 min; MS (ESIpos) m/z=357 [M+H]⁺.

Intermediate 86-Chloro-3-[4-(cyclopropylmethoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]-pyridazine

6-Chloro-3-[4-(cyclopropylmethoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazinewas prepared in analogy to6-chloro-3-[4-(propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazinestarting from 3.5 g (14.9 mmol) of3-bromo-6-chloro-imidazo[1,2-b]pyridazine to yield 1.9 g of the titlecompound after digestion in methanol.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=0.37 (2H), 0.51-0.64 (2H), 1.33 (1H),4.26 (2H), 7.33 (1H), 7.43 (1H), 7.52 (1H), 8.00 (1H), 8.32-8.41 (2H).

LCMS (Method 2): R_(t)=1.37 min; MS (ESIpos) m/z=341 [M+H]⁺.

Intermediate 9 4-Ethoxyfuro[3,2-c]pyridine

To a stirred solution of ethanol (14.7 mL) in anhydrous THF (75 mL) wasadded sodium hydride (60% w/w in oil; 5.51 g) at 0° C. and the mixturewas stirred at 0° C. for 30 min. 4-Chlorofuro[3,2-c]pyridine (5.0 g) wasadded and the mixture was stirred at reflux for 3 hours. Water was addedand the reaction mixture was extracted with ethyl acetate and hexane(1:1 mixture). The organic phase was washed with saturated sodiumchloride solution, dried (sodium sulfate) and the solvent was removed invacuum. Silicagel chromatography gave 5.1 g of the title compound.

¹H-NMR (400 MHz, CHLOROFORM-d), δ [ppm]=1.48 (3H), 4.54 (2H), 6.83-6.90(1H), 7.09 (1H), 7.57 (1H), 8.00 (1H).

LCMS (Method 2): R_(t)=1.02 min; MS (ESIpos) m/z=164 [M+H]⁺.

Intermediate 10 (4-Ethoxyfuro[3,2-c]pyridin-2-yl)boronic acid

To a stirred solution of 4-ethoxyfuro[3,2-c]pyridine (5.1 g) inanhydrous THF (170 mL) was added a solution of n-butyllithium in hexane(18.8 mL; c=2.5 M) at −78° C. The solution was stirred at −78° C. for1.5 h. Triisopropyl borate (9.0 g) was added at −78° C., the mixture wasstirred at −78° C. for 0.5 h and allowed to warm up to room temperaturewithin 16 h. Water was added, the reaction mixture was stirred for 15minutes and the solvent was removed in vacuum. Again, water was addedand the mixture was lyophilized to give 7.7 g of the title compound as acrude product (calculated purity: 84%), which was used without furtherpurification.

LCMS (Method 2): R_(t)=0.7 min; MS (ESIpos) m/z=208 [M+H]⁺.

Intermediate 116-Chloro-3-(4-ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine

To a stirred mixture of 4-ethoxyfuro[3,2-c]pyridine (6.1 g) in anhydrousTHF (90 mL) was added a solution of n-butyllithium in hexane (22 mL;c=2.5 M) at −78 C. The solution was stirred at −78° C. for 1.5 h.Tributyltin chloride (19.2 g) was added at −78° C., and the mixture wasstirred at −78° C. for 0.5 h and allowed to warm up to room temperaturewithin 16 h. Methanol was added, the reaction mixture was stirred for 15minutes. The mixture was filtered through a short silicagel column andthe solvent was removed in vacuum. Silicagel chromatography gave 10.3 gof 4-ethoxy-2-(tributylstannyl)furo[3,2-c]pyridine as a crude productwhich was used without further purification.

To a stirred solution of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (3.3g) in THF (85 mL) was added the crude4-ethoxy-2-(tributylstannyl)furo[3,2-c]pyridine (10.3 g), Pd₂(PPh₃)₂(510 mg), triphenylphosphine (187 mg) and copper (I) iodide (271 mg).The mixture was heated to reflux for 5 h, a mixture of dichloromethaneand methanol (100:1) was added, the mixture was filtered through Celiteand the solvent was removed in vacuum. The residue was titurated withwarm ethanol to give 4.7 g of title compound as a crude product whichwas used without further purification.

LCMS (Method 2): R_(t)=1.36 min; MS (ESIpos) m/z=315 [M+H]⁺.

Intermediate 12tert-Butyl(trans-3-{[3-(4-ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]-pyridazin-6-yl]oxy}cyclobutyl)carbamate

To a stirred suspension of(trans)-tert-butyl-3-hydroxycyclobutyl-carbamat (226 mg) in anhydrousTHF (7 mL) and anhydrous DMF (0.7 mL) was added sodium hydride (60% w/win oil; 48 mg) at 0° C. and the mixture was stirred at room temperaturefor 30 min.6-Chloro-3-(4-ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine(190 mg) was added and the mixture was stirred at room temperature for72 h. The solvent was removed in vacuum. Aminophase-silica-gelchromatography followed by silicagel chromatography gave a solid thatwas triturated with ethyl acetate to give 110 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.36 (9H), 1.41 (3H), 2.52 (4H),4.14-4.30 (1H), 4.48 (2H), 5.32 (1H), 7.04 (1H), 7.33 (1H), 7.37-7.47(2H), 8.01 (1H), 8.11-8.19 (2H).

LCMS (Method 2): R_(t)=1.37 min; MS (ESIpos) m/z=466 [M+H]+.

Intermediate 13(2S)-1-[(3-Bromoimidazo[1,2-b]pyridazin-6-yl)oxy]propan-2-amine

To a stirred suspension of (2S)-2-aminopropan-1-ol (2.91 g) in anhydrousTHF (100 mL) and anhydrous DMF (10 mL) was added sodium hydride (60% w/win oil; 2.07 g) at 0° C. and the mixture was stirred at 0° C. for 30minutes. 3-Bromo-6-chloroimidazo[1,2-b]pyridazine (6.0 g) was added andthe mixture was stirred at room temperature for 16 hours. Water wasadded and the mixture was extracted with a mixture of dichloromethaneand methanol (100:1). The organic phase was dried (sodium sulfate) andthe solvent was removed in vacuum. Silicagel chromatography gave a solidthat was triturated with a mixture of toluene and cyclohexane to give4.9 g of the title compound.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.05 (3H), 1.63 (2H), 3.10-3.23 (1H),4.06 (2H), 6.92 (1H), 7.69 (1H), 8.01 (1H).

LCMS (Method 5): R_(t)=0.81 min; MS (ESIpos) m/z=271; 273 [M+H]⁺.

Intermediate 14 N-Ethylfuro[3,2-c]pyridin-4-amine

A stirred suspension of 4-chlorofuro[3,2-c]pyridine (1.5 g), ethylaminehydrochloride (2.39 g) and Hünig base (5.0 mL) in 2-propanol (7.5 mL)was heated to 130° C. in a microwave oven for 20 h. A half-saturatedsolution of sodium bicarbonate was added and the mixture was extractedwith ethyl acetate. The organic phase was washed with saturated sodiumchloride solution, dried (sodium sulfate) and the solvent was removed invacuum. Silicagel chromatography gave 793 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.15 (3H), 3.40 (2H), 6.73 (1H), 6.87(1H), 7.03 (1H), 7.75 (1H), 7.78 (1H).

LCMS (Method 5): R_(t)=0.86 min; MS (ESIpos) m/z=163 [M+H]⁺.

Intermediate 15 tert-Butyl ethyl(furo[3,2-c]pyridin-4-yl)carbamate

To a stirred solution of N-ethylfuro[3,2-c]pyridin-4-amine (940 mg) andHünig base (3.0 mL) in THF (50 mL) was added di-tert-butyl dicarbonate(1.52 g) and the mixture was stirred at 65° C. for 24 h. Ahalf-saturated solution of sodium bicarbonate was added and the mixturewas extracted with ethyl acetate. The organic phase was washed withsaturated sodium chloride solution, dried (sodium sulfate) and thesolvent was removed in vacuum. Silicagel chromatography gave 1.38 g ofthe title compound.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.09 (3H), 1.35 (9H), 3.80 (2H), 6.74(1H), 7.52 (1H), 8.04 (1H), 8.25 (1H).

LCMS (Method 5): R_(t)=1.20 min; MS (ESIpos) m/z=263 [M+H]⁺.

Intermediate 16{4-[(tert-Butoxycarbonyl)(ethyl)amino]furo[3,2-c]pyridin-2-yl}boronicacid

To a stirred solution of tert-butylethyl(furo[3,2-c]pyridin-4-yl)carbamate (1.86 g) in anhydrous THF (20mL) was added a solution of n-butyllithium in hexane (3.8 mL; c=2.5 M)at −78° C. The solution was stirred at −78° C. for 1.5 h. Triisopropylborate (1.92 g) was added at −78° C., and the mixture was stirred at−78° C. for 0.5 h and allowed to warm up to room temperature within 16h. Water was added, the reaction mixture was stirred for 15 minutes andthe solvent was removed in vacuum. Again, water was added and themixture was lyophilized to give 1.98 g of the title compound as a crudeproduct which was used without purification.

LCMS (Method 5): R_(t)=0.46 min; MS (ESIpos) m/z=307 [M+H]⁺.

Intermediate 17 4-(Cyclobutyloxy)furo[3,2-c]pyridine

In an ice bath, 4.98 g (69 mmol) cyclobutanol were added to 2.7 g (69mmol) sodium hydride (60% dispersion in mineral oil) in 160 mL ofanhydrous THF. The mixture was stirred for 15 min at 0° C. 4 g (26 mmol)4-chlorofuro[2,3-c]pyridine were added an the mixture was stirred at 80°C. for 24 h.

5 mL of water were carefully added and the mixture was concentratedunder reduced pressure. The residue was taken up in 200 mL of water andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate and evaporated.

The crude product was purified by flash chromatography to give 3.75 g ofthe title compound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.59-1.74 (1H), 1.81 (1H), 2.06-2.18(2H), 2.39-2.48 (2H), 5.32 (1H), 6.97 (1H), 7.26-7.32 (1H), 7.97 (1H),8.01 (1H).

LCMS (Method 2): R_(t)=1.26 min; MS (ESIpos) m/z=190 [M+H]+.

Intermediate 18 [4-(Cyclobutyloxy)furo[3,2-c]pyridin-2-yl]boronic acid

To a stirred solution of 3.7 g (19.7 mmol)4-cyclobutoxyfuro[3,2-c]pyridine in 202 mL of anhydrous THF were added11.7 mL (29 mmol) of a 2.5 M solution of n-butyllithium in hexane at−78° C. The solution was stirred at −78° C. for 1.5 h. 6.8 mL (29 mmol)triisopropyl borate were added at −78° C. and the mixture was stirred atroom temperature for 2 h. Water was added and the solvent was removed invacuum to yield 7.2 g the title compound as a crude product which wasused without further purification.

LCMS (Method 2): R_(t)=0.88 min; MS (ESIpos) m/z=234 [M+H]⁺.

Intermediate 19(2R)-1-[(3-Bromoimidazo[1,2-b]pyridazin-6-yl)oxy]propan-2-amine

(2R)-1-[(3-Bromoimidazo[1,2-b]pyridazin-6-yl)oxy]propan-2-amine wasprepared in analogy to its enantiomer(2S)-1-[(3-bromoimidazo[1,2-b]pyridazin-6-yl)oxy]propan-2-amine.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.05 (3H), 3.17 (1H), 4.06 (2H), 6.92(1H), 7.69 (1H), 8.01 (1H).

LCMS (Method 4): R_(t)=0.55 min; MS (ESIpos) m/z=271; 273 [M+H]+.

EXAMPLES Example 1(1S)-2-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-phenylethanamine

At 0° C. 81 mg (0.59 mmol) (S)-2-phenylglycinol were added to 23 mg(0.59 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 80 mg (0.3 mmol) of6-chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine were added.The ice bath was removed and the mixture was stirred for 18 h at 40° C.

The reaction mixture was poured into half saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, and concentrated. The residue waspurified by HPLC to give 29 mg of the title compound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=4.42-4.49 (1H), 4.55-4.70 (2H), 7.04(1H), 7.27-7.34 (1H), 7.38 (2H), 7.54 (2H), 7.67 (1H), 7.74 (1H),8.16-8.23 (3H), 8.51 (1H), 8.98 (1H).

LC-MS (Method 3): R_(t)=0.53 min; MS (ESIpos) m/z=372 [M+H]⁺.

Example 2trans-3-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}cyclobutanamine

At 0° C. 91 mg (0.74 mmol) trans-3-aminocylcobutanol hydrochloride wereadded to 44 mg (1.11 mmol) sodium hydride (60% in mineral oil) in 4 mLanhydrous THF. After 15 min of stirring on the ice bath, 150 mg (0.37mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 72h at 40° C. The mixture was again cooled to 0-5° C. additional amountsof 68 mg (0.56 mmol) trans-3-aminocylcobutanol hydrochloride and 29 mg(0.74 mmol) sodium hydride (60% in mineral oil) werde added. Stirring at40° C. was continued for 18 h.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to give 61 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.51-2.58 (4H), 3.39-3.48 (2H),3.79-3.85 (1H), 4.06 (3H), 5.39-5.49 (1H), 7.05 (1H), 7.35-7.42 (1H),7.48 (1H), 8.07 (1H), 8.13-8.22 (2H).

LC-MS (Method 3): Rt=0.69 min; MS (ESIpos) m/z=352 [M+H]⁺.

Example 3(2R)-1-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}propan-2-amine

At 0° C. 39 mg (0.52 mmol) (R)-2-aminopropan-1-ol were added to 21 mg(0.52 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 105 mg (0.26 mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 18h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to give 45 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.19 (3H), 3.37-3.49 (1H), 4.00 (3H),4.19-4.39 (2H), 7.02 (1H), 7.35 (1H), 7.42 (1H), 8.03 (1H), 8.10-8.19(2H).

LC-MS (Method 3): R_(t)=0.74 min; MS (ESIpos) m/z=340 [M+H]⁺.

Example 4(1S)-2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-phenylethanamine

At 0° C. 71 mg (0.52 mmol) (S)-2-phenylglycinol were added to 21 mg(0.52 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 105 mg (0.26 mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 19h at 40° C.

The reaction mixture was poured into half saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, and concentrated. The residue waspurified by HPLC to give 4 mg of the title compound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=4.02 (3H), 4.35-4.52 (2H), 4.55-4.67(1H), 6.98-7.09 (1H), 7.38 (5H), 7.48 (1H), 7.52-7.59 (2H), 8.02-8.09(1H), 8.12-8.22 (2H).

LC-MS (Method 3): R_(t)=0.86 min; MS (ESIpos) m/z=402 [M+H]⁺.

Example 5(2S)-1-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}propan-2-amine

At 0° C. 39 mg (0.52 mmol) (S)-2-aminopropan-1-ol were added to 21 mg(0.52 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 105 mg (0.26 mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 18h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to give 46 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.19 (3H), 3.39-3.45 (1H), 4.00 (3H),4.21-4.38 (2H), 7.02 (1H), 7.35 (1H), 7.42 (1H), 8.03 (1H), 8.11-8.18(2H).

LC-MS (Method 3): R_(t)=0.74 min; MS (ESIpos) m/z=340 [M+H]⁺.

Example 6(2R)-2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}propan-1-amine

At 0° C. 39 mg (0.52 mmol) (R)-1-aminopropan-2-ol were added to 21 mg(0.52 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 105 mg (0.26 mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 18h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to give 48 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.43 (3H), 2.93 (2H), 4.01 (3H),5.06-5.18 (1H), 6.98 (1H), 7.35 (1H), 7.41 (1H), 8.03 (1H), 8.11-8.17(2H).

LC-MS (Method 3): R_(t)=0.76 min; MS (ESIpos) m/z=340 [M+H]⁺.

Example 7(1R)-2-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-phenylethanamine

At 0° C. 82 mg (0.6 mmol) (R)-2-phenylglycinol were added to 24 mg (0.6mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF. After15 min of stirring on the ice bath, 81 mg (0.3 mmol) of6-chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine were added.The ice bath was removed and the mixture was stirred for 18 h at 40° C.

The reaction mixture was poured into half saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, and concentrated. The residue waspurified by HPLC to give 42 mg of the title compound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=4.45 (1H), 4.53-4.69 (2H), 7.04 (1H),7.26-7.32 (1H), 7.34-7.41 (2H), 7.54 (2H), 7.67 (1H), 7.74 (1H),8.15-8.24 (2H), 8.50 (1H), 8.98 (1H).

LC-MS (Method 3): R_(t)=0.52 min; MS (ESIpos) m/z=372 [M+H]⁺.

Example 8(2R)-2-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-1-amine

At 0° C. 33 mg (0.44 mmol) (R)-1-aminopropan-2-ol were added to 14 mg(0.59 mmol) sodium hydride (60% in mineral oil) in 5 mL anhydrous THF.After 15 min of stirring on the ice bath, 80 mg (0.3 mmol) of6-chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine were added.The ice bath was removed and the mixture was stirred for 16 h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The whole mixture was concentrated and purified by HPLCfollowed by flash chromatography and preparative thin layerchromatography to give 8 mg of the title compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.43 (3H), 2.85-2.92 (2H), 5.13-5.26(1H), 6.97-7.04 (1H), 7.59-7.65 (1H), 7.68-7.74 (1H), 8.11-8.21 (2H),8.43-8.51 (1H), 8.98-9.04 (1H).

LC-MS (Method 3): R_(t)=0.47 min; MS (ESIpos) m/z=310 [M+H]⁺.

Example 9(1R)-2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-phenylethanamine

At 0° C. 71 mg (0.52 mmol) (R)-2-phenylglycinol were added to 21 mg(0.52 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 105 mg (0.26 mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 18h at 40° C.

The reaction mixture was poured into half saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, and concentrated. The residue waspurified by HPLC to give 69 mg of the title compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), a [ppm]=3.98 (3H), 4.42 (2H), 4.53-4.64 (1H),7.00 (1H), 7.25-7.40 (4H), 7.43 (1H), 7.52 (2H), 8.02 (1H), 8.10-8.17(2H).

LC-MS (Method 3): R_(t)=0.88 min; MS (ESIpos) m/z=402 [M+H]⁺.

Example 10(2R,3R)-3-(Benzyloxy)-1-{[3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]-pyridazin-6-yl]oxy}butan-2-amine

At 0° C. 84 mg (0.43 mmol) (2R,3R)-2-amino-3-(benzyloxy)butan-1-ol wereadded to 17 mg (0.43 mmol) sodium hydride (60% in mineral oil) in 3 mLanhydrous THF and 1 mL DMF. After 15 min of stirring on the ice bath,100 mg (0.22 mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 17h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to give 20 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.24 (3H), 1.73-2.01 (1H), 3.06-3.20(1H), 3.64-3.74 (1H), 3.93 (3H), 4.24-4.37 (1H), 4.39-4.53 (2H), 4.61(1H), 6.98 (1H), 7.06-7.21 (3H), 7.29 (2H), 7.36 (1H), 7.49 (1H), 8.03(1H), 8.10-8.18 (2H).

LC-MS (Method 3): R_(t)=0.90 min; MS (ESIpos) m/z=460 [M+H]⁺.

Example 11(2R)-1-(Benzyloxy)-3-{[3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]-pyridazin-6-yl]oxy}propan-2-amine

At 0° C. 196 mg (1.1 mmol) (R)-2-amino-3-benzyloxypropan-1-ol were addedto 43 mg (1.1 mmol) sodium hydride (60% in mineral oil) in 8 mLanhydrous THF. After 15 min of stirring on the ice bath, 250 mg (0.54mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 16h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to give 38 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=3.37 (1H), 3.51 (2H), 3.95 (3H), 4.35(1H), 4.47 (1H), 4.53 (2H), 7.01 (1H), 7.15-7.33 (5H), 7.36 (1H), 7.48(1H), 8.03 (1H), 8.15 (2H).

LC-MS (Method 3): R_(t)=0.87 min; MS (ESIpos) m/z=446 [M+H]⁺.

Example 12(2S)-1-{[3-(Furo[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine

To a stirred suspension of (2S)-2-aminopropan-1-ol (27 mg, 354 μmol) inanhydrous THF (3.5 mL) was added sodium hydride (60% w/w in oil; 23 mg)at 0° C. and the mixture was stirred at 0° C. for 30 minutes.6-chloro-3-(furo[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (80 mg, 177μmol) was added and the mixture was stirred at room temperature for 2 h.A half-saturated aqueous solution of sodium chloride was added and themixture was extracted with ethyl acetate. The organic phase was dried(sodium sulfate) and the solvent was removed in vacuum.Aminophase-silica-gel chromatography gave a solid that was trituratedwith a mixture of ethanol and hexane to give 35 mg of the titlecompound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=1.16 (d, 3H), 1.72 (br. s., 2H),3.24-3.32 (m, 1H), 4.28 (d, 2H), 7.12 (d, 1H), 7.65 (d, 1H), 7.78 (dd,1H), 8.22 (d, 1H), 8.28 (s, 1H), 8.43 (d, 1H), 8.99 (s, 1H).

LCMS (Method 3): R_(t)=0.74 min; MS (ESIpos) m/z=310 [M+H]+.

Example 13trans-3-{[3-(Furo[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-cyclobutanaminesalt with formic acid

To a stirred suspension of trans-3-aminocyclobutanol hydrochloride (57.5mg, 465 μmol) in anhydrous THF (3.0 mL) and anhydrous DMF (1.5 mL) wasadded sodium hydride (60% w/w in oil; 27 mg) at 0° C. and the mixturewas stirred at 0° C. for 30 minutes.6-Chloro-3-(furo[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (70 mg, 155μmol) was added and the mixture was stirred at room temperature for 16h. A half-saturated solution of sodium chloride was added and themixture was extracted with ethyl acetate. The solvent was removed invacuum. Aminophase-silica-gel chromatography gave a solid that wastriturated with dichloromethane. Preparative reverse phase HPLC gave 21mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, detected signals of the formic acid salt): 5[ppm]=2.52-2.69 (m, 4H), 3.79 (br. s., 1H), 5.49-5.67 (m, 1H), 7.09 (d,1H), 7.67 (s, 1H), 7.79 (d, 1H), 8.22 (d, 1H), 8.27 (s, 1H), 8.37 (br.s., 1H), 8.44 (d, 1H), 8.98 (s, 1H).

LCMS (Method 3): Rt=0.47 min; MS (ESIpos) m/z=322 [M+H]+.

Example 14trans-3-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutanaminesalt with formic acid

To a stirred suspension of trans-3-aminocyclobutanol hydrochloride (110mg) in anhydrous THF (6 mL) and anhydrous DMF (3 mL) was added sodiumhydride (60% w/w in oil; 52 mg) at 0° C. and the mixture was stirred at0° C. for 30 minutes.6-Chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (80 mg) andpotassium carbonate (204 mg) was added and the mixture was stirred atroom temperature for 72 h. A half-saturated solution of sodium chloridewas added and the mixture was extracted with ethyl acetate.Aminophase-silica-gel chromatography followed by preparative reversephase HPLC gave a solid that was triturated with dichloromethane to give40 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆, detected signals of the formic acid salt), δ[ppm]=2.50-2.64 (4H), 3.76 (1H), 5.59 (1H), 7.04 (1H), 7.66-7.74 (2H),8.13-8.21 (2H), 8.39 (1H), 8.46 (1H), 9.03 (1H).

LC-MS (Method 2): R_(t)=0.47 min; MS (ESIpos) m/z=322 [M+H]⁺.

Example 15(2R)-2-Amino-3-{[3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-1-C₁

To a solution of 60 mg (0.14 mmol)(2R)-1-(benzyloxy)-3-{[3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-aminein 5 mL of methanol were added 43 mg palladium on charcoal (containing10% palladium) and 0.67 μL of 4 M hydrochloric acid in dioxane. Theflask was flushed with hydrogen gas and equipped with a hydrogenballoon. The mixture was stirred vigorously for 1 day.

The catalyst was filtered off and washed with methanol. The filtrate wasevaporated and the obtained crude product was purified by HPLC to give 5mg of the title compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=3.15-3.24 (2H), 3.43-3.55 (2H), 4.02(3H), 4.28-4.37 (1H), 4.39-4.49 (1H), 6.99-7.07 (1H), 7.33-7.39 (1H),7.48 (1H), 8.02-8.07 (1H), 8.13-8.19 (2H).

LCMS (Method 3): R_(t)=0.65 min; MS (ESIpos) m/z=356 [M+H]⁺.

Example 163-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylpropan-1-amine

At 0° C. 96 mg (1.1 mmol) 3-amino-2-methylpropan-1-ol were added to 43mg (1.1 mmol) sodium hydride (60% in mineral oil) in 8 mL anhydrous THF.After 15 min of stirring on the ice bath, 250 mg (0.54 mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 72h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, andconcentrated. The residue was purified by HPLC to give 122 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.07 (3H), 4.01 (3H), 4.41 (2H), 7.04(1H), 7.36 (1H), 7.50 (1H), 8.04 (1H), 8.12-8.20 (2H).

LC-MS (Method 3): R_(t)=0.70 min; MS (ESIpos) m/z=354 [M+H]⁺.

Example 17(2R)-{[3-(Furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine

At 0° C. 41 mg (0.56 mmol) (R)-2-aminopropan-1-ol were added to 22 mg(0.56 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 80 mg (0.29 mmol) of6-chloro-3-(furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine were added.The ice bath was removed and the mixture was stirred for 72 h at 40° C.

The reaction mixture was poured into saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was purified byHPLC to give 53 mg of the title compound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.19 (3H), 3.39 (1H), 4.29-4.39 (2H),7.08 (1H), 7.34 (1H), 7.66 (1H), 8.05 (1H), 8.20 (1H), 8.23 (1H), 8.51(1H).

LC-MS (Method 3): Rt=0.57 min; MS (ESIpos) m/z=310 [M+H]⁺.

Example 18(1S,3R)-3-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}cyclopentanamine

At 0° C. 36 mg (0.26 mmol) (1R,3S)-3-aminocyclopentanol hydrochloridewere added to 16 mg (0.39 mmol) sodium hydride (60% in mineral oil) in 4mL anhydrous THF. After 15 min of stirring on the ice bath, 129 mg (0.26mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 15h at 40° C.

0.07 mL (0.53 mmol) of triethylamine were added and the mixture wasstirred at 40° C. for another 7 h.

In a separate flask, 19 mg (0.13 mmol) of (1R,3S)-3-aminocyclopentanolhydrochloride were added at 0° C. to 8 mg (0.2 mmol) sodium hydride (60%in mineral oil) in 1 mL anhydrous DMF. This mixture was added to thereaction and the resulting mixture was stirred at 40° C. for another 16h.

In a separate flask, 19 mg (0.13 mmol) of (1R,3S)-3-aminocyclopentanolhydrochloride were added at 0° C. to 8 mg (0.2 mmol) sodium hydride (60%in mineral oil) in 1 mL anhydrous DMF. Again, this mixture was added tothe reaction and the resulting mixture was stirred at 40° C. for another16 h.

The reaction mixture was poured into saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and concentrated. The residue was purified byHPLC to give 54 mg of the title compound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.65 (1H), 1.72-1.81 (1H), 1.97 (1H),2.06-2.15 (2H), 2.52-2.61 (1H), 3.46 (1H), 4.04 (3H), 5.37-5.44 (1H),7.02 (1H), 7.38 (1H), 7.48 (1H), 8.06 (1H), 8.14-8.19 (2H).

LC-MS (Method 3): R_(t)=0.77 min; MS (ESIpos) m/z=366 [M+H]⁺.

Example 19(2S)-1-({3-[4-(Propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)propan-2-amine

At 0° C. 42 mg (0.55 mmol) (2S)-aminopropan-1-ol were added to 22 mg(0.55 mmol) sodium hydride (60% in mineral oil) in 3.6 mL anhydrous THF.After 15 min of stirring on the ice bath, 90 mg (0.27 mmol) of6-chloro-3-[4-(propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 18h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, andconcentrated. The residue was purified by HPLC to give 49 mg of thetitle compound as solid material.

¹H-NMR (600 MHz, DMSO-d₆): δ [ppm]=1.20 (3H), 1.39 (6H), 3.47 (1H), 4.21(1H), 4.41 (1H), 5.45 (1H), 7.09 (1H), 7.35 (1H), 7.51 (1H), 8.05 (1H),8.18 (1H), 8.21 (1H).

LC-MS (Method 3): Rt=0.88 min; MS (ESIpos) m/z=368 [M+H]⁺.

Example 20(2S)-1-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine

At 0° C. 44 mg (0.59 mmol) (2S)-2-aminopropan-1-ol were added to 24 mg(0.59 mmol) sodium hydride (60% in mineral oil) in 5 mL anhydrous THF.After 15 min of stirring on the ice bath, 80 mg (0.27 mmol) of6-chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine were added.The ice bath was removed and the mixture was stirred for 16 h at 40° C.

The reaction mixture was poured into saturated ammonium chloridesolution and extracted with ethyl acetate. The organic layer wasconcentrated and purified by HPLC to give 10 mg of the title compound assolid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.13 (3H), 4.26 (2H), 7.06 (1H),7.64-7.74 (2H), 8.12-8.25 (2H), 8.47 (1H), 9.01 (1H).

Example 21trans-4-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}cyclohexanaminesalt with formic acid

To a stirred suspension of trans-4-aminocyclohexanol hydrochloride (56mg) in amhydrous THF (2 mL) and anhydrous DMF (2 mL) was added sodiumhydride (60% w/w in oil; 31 mg) at 0° C. and the mixture was stirred at0° C. for 30 minutes.6-Chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine(75 mg) was added and the mixture was stirred at reflux for 30 minutes.Solids were removed by filtration and the solvent was removed in vacuum.The residue was dissolved in DMSO and formic acid (100:0.1). Preparativereverse phase HPLC gave a solid that was triturated with ethanol to give60 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆, signals of the formic acid salt), δ[ppm]=1.35-1.66 (4H), 1.99 (2H), 2.33 (2H), 2.80-2.97 (1H), 4.02 (3H),4.83-5.01 (1H), 6.99 (1H), 7.35 (1H), 7.47 (1H), 8.03 (1H), 8.10-8.20(2H), 8.44 (4H).

LC-MS (Method 3): R_(t)=0.80 min; MS (ESIpos) m/z=380 [M+H]⁺.

Example 221-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylpropan-2-amine

At 0-5° C. 59 mg (0.66 mmol) 2-amino-2-methylpropan-1-ol were added to27 mg (0.67 mmol) sodium hydride (60% in mineral oil) in 5 mL anhydrousDMF. After 5 min of stirring on the ice bath, 100 mg (0.33 mmol)6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and it was stirred 3 hours at roomtemperature.

The reaction mixture was poured into half saturated ammonium chloridesolution.

It was extracted four times with ethyl acetate. The combined organicphases were washed with brine, dried over magnesium sulfate andconcentrated. The residue was purified by HPLC yielding 55 mg (47%)product.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.18 (6H), 4.01 (3H), 4.18 (2H), 7.05(1H), 7.36 (1H), 7.45 (1H), 8.04 (1H), 8.11-8.19 (2H).

LC-MS (Method 2): Rt=0.73 min; MS (ESIpos) m/z=353 [M+H]⁺.

Example 233-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-phenylpropan-1-amine

At 0° C. 203 mg (1.1 mmol) 3-amino-2-phenylpropan-1-ol hydrochloridewere added to 86 mg (2.1 mmol) sodium hydride (60% in mineral oil) in 8mL anhydrous THF. After 15 min of stirring on the ice bath, 250 mg (0.54mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 72h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, andconcentrated. The residue was purified by HPLC to give 83 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=3.08-3.14 (1H), 3.15-3.24 (1H),3.37-3.50 (1H), 4.03 (3H), 4.65-4.85 (2H), 6.99-7.10 (1H), 7.25-7.46(6H), 7.51-7.58 (1H), 8.03-8.11 (1H), 8.13-8.22 (2H).

LC-MS (Method 3): R_(t)=0.80 min; MS (ESIpos) m/z=416 [M+H]⁺.

Example 24trans-3-({3-[4-(2,2-Dimethylpropoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]-pyridazin-6-yl}oxy)cyclobutanamine

At 0° C. 94 mg (0.5 mmol) tert-butyl(trans-3-hydroxycyclobutyl)carbamatewere added to 20 mg (0.5 mmol) sodium hydride (60% in mineral oil) in 6mL anhydrous THF. After 15 min of stirring on the ice bath, 90 mg (0.25mmol) of6-chloro-3-[4-(2,2-dimethylpropoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 19h at 40° C.

The reaction mixture was poured into half saturated aqueous sodiumchloride solution and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, and concentrated.

The obtained crude material was taken up in 10 mL dichloromethane. 5 mLtrifluoro acetic acid were added and the mixture was stirred for 10 minat room temperature.

5 mL ammonia (25% in water) were carefully added. Half saturated aqueoussodium chloride solution was added. The mixture was extracted withdichlormethane. The organic layer was dried over sodium sulfate andconcentrated.

The crude material was purified by HPLC to give 30 mg of the titlecompound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.08 (9H), 2.24-2.37 (2H), 2.54 (2H),3.66-3.78 (1H), 4.15 (2H), 5.34-5.45 (1H), 7.06 (1H), 7.37 (1H), 7.55(1H), 8.03 (1H), 8.15-8.22 (2H).

LC-MS (Method 4): R_(t)=0.96 min; MS (ESIpos) m/z=408 [M+H]⁺.

Example 25(2S)-1-({3-[4-(Cyclopropylmethoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]-pyridazin-6-yl}oxy)propan-2-amine

At 0° C. 41 mg (0.54 mmol) (2S)-2-aminopropan-1-ol were added to 21 mg(0.54 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 120 mg (0.27 mmol) of6-chloro-3-[4-cyclopropylmethoxy)-furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 18h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was concentrated and purified by HPLC,followed by flash chromatography to give 40 mg of the title compound assolid material.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.38-0.44 (2H), 0.55-0.62 (2H),1.15-1.21 (3H), 1.29-1.37 (1H), 3.39-3.45 (1H), 4.20 (1H), 4.32 (2H),4.37 (1H), 7.08 (1H), 7.37 (1H), 7.53 (1H), 8.03 (1H), 8.18 (1H), 8.20(1H).

LC-MS (Method 2): R_(t)=0.83 min; MS (ESIpos) m/z=380 [M+H]⁺.

Example 26(2R)-1-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine

At 0° C. 44 mg (0.59 mmol) (2R)-2-aminopropan-1-ol were added to 23 mg(0.59 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 80 mg (0.3 mmol) of6-chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine were added.The ice bath was removed and the mixture was stirred for 16 h at 40° C.

The reaction mixture was poured into saturated ammonium chloridesolution and extracted with ethyl acetate. The organic layer wasconcentrated and purified by HPLC to give 19 mg of the title compound assolid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.17 (3H), 1.65-1.83 (2H), 3.17-3.25(1H), 4.26-4.33 (2H), 7.07-7.13 (1H), 7.68-7.77 (2H), 8.22 (2H),8.47-8.53 (1H), 9.01-9.08 (1H).

LC-MS (Method 2): R_(t)=0.44 min; MS (ESIpos) m/z=310 [M+H]⁺.

Example 271-[3-({[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}methyl)oxetan-3-yl]methanamine

At 0° C. 31 mg (0.27 mmol) [3-(aminomethyl)oxetan-3-yl]methanol wereadded to 11 mg (0.27 mmol) sodium hydride (60% in mineral oil) in 2 mLanhydrous THF. After 15 min of stirring on the ice bath, 54 mg (0.13mmol) of6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 72h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, andconcentrated. The residue was purified by HPLC to give 15 mg of thetitle compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.97 (2H), 4.02 (3H), 4.39-4.50 (4H),4.69 (2H), 7.05 (1H), 7.36 (1H), 7.55 (1H), 8.04 (1H), 8.16 (2H).

LC-MS (Method 3): R_(t)=0.69 min; MS (ESIpos) m/z=382 [M+H]⁺.

Example 28trans-3-{[3-(Furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutanamine

At 0° C. 104 mg (0.6 mmol)tert-butyl(trans-3-hydroxycyclobutyl)carbamate were added to 22 mg (0.56mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF. After15 min of stirring on the ice bath, 80 mg (0.28 mmol) of6-chloro-3-(furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine were added.The ice bath was removed and the mixture was stirred for 72 h at 40° C.

The reaction mixture was poured into saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic layer was driedover sodium sulfate, and concentrated.

The obtained crude material was taken up in 2 mL dichloromethane. 1 mLtrifluoro acetic acid was added and the mixture was stirred for 15 minat room temperature.

2 mL ammonia (25% in water) were carefully added. Water was added. Themixture was extracted with a 95:5 mixture of dichlormethane andmethanol. The organic layer was dried over magnesium sulfate andconcentrated.

The crude material was purified by HPLC to give 48 mg of the titlecompound as solid material.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=2.54-2.60 (4H), 3.80 (1H), 5.54 (1H),7.07 (1H), 7.34 (1H), 7.65 (1H), 8.05 (1H), 8.19 (1H), 8.22-8.27 (1H),8.52 (1H).

LC-MS (Method 3): Rt=0.58 min; MS (ESIpos) m/z=322 [M+H]⁺.

Example 29trans-3-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutanamine

At 0° C. 84 mg (0.68 mmol) trans-3-aminocylcobutanol hydrochloride in 2mL of a 1:1 mixture of anhydrous THF and anhydrous DMF were added to 41mg (1 mmol) sodium hydride (60% in mineral oil) in 2 mL anhydrous THF.After 15 min of stirring on the ice bath, 100 mg (0.34 mmol) of6-chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine were added.The ice bath was removed and the mixture was stirred for 72 h at 40° C.

The reaction mixture was poured into water and extracted with ethylacetate. The combined organic phases and the aqueous phases wereconcentrated separately and then they were combined to purify theresidue by HPLC. to give 22 mg of the title compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.46 (4H), 3.55-3.72 (1H), 5.33-5.55(1H), 6.95-7.11 (1H), 7.57-7.80 (2H), 8.10-8.26 (2H), 8.41-8.58 (1H),8.95-9.11 (1H).

LC-MS (Method 3): R_(t)=0.48 min; MS (ESIpos) m/z=322 [M+H]⁺.

Example 30(2S)-1-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-3-methylbutan-2-amine

To a stirred suspension of (S)-(+)-2-amino-3-methyl-1-butanol (53 mg) inanhydrous THF (5 mL) was added sodium hydride (60% w/w in oil; 34 mg) at0° C. and the mixture was stirred at 0° C. for 30 minutes.6-Chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine (70 mg) wasadded and the mixture was stirred at room temperature for 72 hours. Ahalf-saturated solution of sodium chloride was added and the mixture wasextracted with ethyl acetate. The solution was dried (sodium sulfate)and the solvent was removed in vacuum. Aminophase-silica-gelchromatography gave a solid that was triturated with a mixture ofethanol and hexane to give 48 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=0.95 (6H), 1.52 (2H), 1.72-1.89 (1H),2.87-2.99 (1H), 4.23-4.35 (1H), 4.36-4.47 (1H), 7.06 (1H), 7.63 (1H),7.69 (1H), 8.09-8.21 (2H), 8.46 (1H), 8.97 (1H).

LC-MS (Method 2): R_(t)=0.51 min; MS (ESIpos) m/z=338 [M+H]⁺.

Example 31(1S,2S)-2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}cyclopentanamine

At 0-5° C. 137 mg (1.00 mmol) (1S,2S)-2-aminocyclopentanol hydrochloridewere added to 79.8 mg (2.00 mmol) sodium hydride (60% in mineral oil) in7 mL anhydrous DMF. After 5 minutes of stirring on the ice bath, 150 mg(0.50 mmol)6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and it was stirred 3 h at roomtemperature. The reaction mixture was poured into water. It wasconcentrated. To the residue were added 1 mL DMF, 3 mL methanol und 0.5mL water. It was heated under reflux and from the hot solution theinsoluble material was filtered off using a Whatman filter. The filtratewas concentrated and dissolved in a mixture of 1 mL DMF and 3 mLmethanol. The insoluble material was filtered of and discarded. Thefiltrate was purified by HPLC to afford 43 mg (23%) product.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.37-1.49 (1H), 1.61-1.88 (3H),1.88-2.03 (1H), 2.25-2.38 (1H), 3.40-3.48 (1H), 4.01 (3H), 4.96-5.03(1H), 6.98 (1H), 7.36 (1H), 7.53 (1H), 8.03 (1H), 8.10-8.18 (2H).

LC-MS (Method 2): R_(t)=0.76 min; MS (ESIpos) m/z=365 [M+H]⁺.

Example 32(2S)-1-{[3-(4-Ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-propan-2-amine

To a stirred solution of(2S)-1-[(3-bromoimidazo[1,2-b]pyridazin-6-yl)oxy]propan-2-amine (5.60 g)in 1-propanol (100 mL) was added 2M potassium carbonate solution (31ml), crude (4-ethoxyfuro[3,2-c]pyridin-2-yl)boronic acid (84% w/w; 7.64g), triphenylphosphine (542 mg) and PdCl₂(PPh₃)₂ (1.45 g). The mixturewas heated to reflux for 2 h. The warm mixture was filtered throughCelite the solvent was removed in vacuum. A half-saturated solution ofsodium bicarbonate was added and the mixture was extracted with amixture of dichloromethane and methanol. The organic phase was washedwith saturated sodium chloride solution, dried (sodium sulfate) and thesolvent was removed in vacuum. Silicagel chromatography gave a solidthat was triturated with a mixture of dichloromethane and hexane to give4.17 g of the title compound.

¹H-NMR (300 MHz, DMSO-d₆, detected signals), δ [ppm]=1.13 (3H), 1.36(3H), 3.29-3.42 (1H), 4.14 (1H), 4.29 (1H), 4.45 (2H), 7.02 (1H), 7.31(1H), 7.42 (1H), 7.99 (1H), 8.10-8.17 (2H).

LC-MS (Method 5): Rt=1.04 min; MS (ESIpos) m/z=354 [M+H]⁺.

Example 332-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-3-phenylpropan-1-amine

At 0-5° C. 124.5 mg (0.66 mmol) 1-amino-3-phenylpropan-2-olhydrochloride were added to 58.5 mg (1.46 mmol) sodium hydride (60% inmineral oil) in 4.5 mL anhydrous DMF. After 5 minutes of stirring on theice bath, 100 mg (0.33 mmol)6-chloro-3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazinewere added. The ice bath was removed and it was stirred 3 h at roomtemperature. The reaction mixture was poured into half saturatedammonium chloride solution. 25 mL ethyl acetate were added and thelayers were separated. The insoluble material in the aqueous phase wasfiltered off and washed with ethyl acetate. The aqueous phase wasextracted three times with ethyl acetate. The combined organic phaseswere washed with brine, dried over magnesium sulfate and concentrated.The residue was purified by HPLC yielding 9 mg (6%) product.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=2.79-3.08 (3H), 3.17-3.25 (1H), 4.05(3H), 5.31-5.42 (1H), 7.00 (1H), 7.16-7.28 (3H), 7.29-7.39 (3H), 7.51(1H), 8.06 (1H), 8.11-8.19 (2H).

LC-MS (Method 4): R_(t)=0.89 min; MS (ESIpos) m/z=415 [M+H]+.

Example 34(2S)-1-({3-[4-(2,2-Dimethylpropoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]-pyridazin-6-yl}oxy)propan-2-amine

At 0° C. 39 mg (0.5 mmol) (2S)-2-aminopropan-1-ol were added to 20 mg(0.5 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF.After 15 min of stirring on the ice bath, 90 mg (0.25 mmol) of6-chloro-3-[4-(2,2-dimethylpropoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 19h at 40° C.

The reaction mixture was poured into water and extracted consecutivelywith dichloromethane and ethyl acetate. The combined organic layers weredried over sodium sulfate, and concentrated. The obtained material wasdigested in methanol to give 64 mg of the title compound as solidmaterial.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.06 (9H), 1.13 (3H), 1.69 (2H)3.34-3.38 (1H), 4.12-4.18 (3H), 4.35 (1H), 7.09 (1H), 7.36 (1H), 7.58(1H), 8.03 (1H), 8.18 (1H), 8.20 (1H.)

LC-MS (Method 3): R_(t)=0.98 min; MS (ESIpos) m/z=396 [M+H]⁺.

Example 352-{6-[(trans-3-Aminocyclobutyl)oxy]imidazo[1,2-b]pyridazin-3-yl}furo[3,2-c]-pyridin-4-ol

To 325 mg (0.93 mmol)trans-3-{[3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo-[1,2-b]pyridazin-6-yl]oxy}cyclobutanaminein 5 mL dioxane were added 0.46 mL of a 4 M solution of HCl in dioxane.The mixture was stirred for 1 h at room temperature.

The solvent was evaporated. The obtained material was digested inmethanol. The obtained solid material was subjected to HPLC purificationto give 43 mg of the title compound as solid material.

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=2.58-2.72 (3H), 3.91 (1H), 5.42-5.50(1H), 6.75 (1H), 7.03 (1H), 7.38 (1H), 7.44 (1H), 8.09 (1H), 8.18 (1H).

LC-MS (Method 3): R_(t)=0.98 min; MS (ESIpos) m/z=396 [M+H]⁺.

Example 36trans-3-{[3-(4-Ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-cyclobutanamine

To a stirred suspension oftert-butyl(trans-3-{[3-(4-ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutyl)carbamate(110 mg) in dichloromethane (10 mL) was added TFA (0.5 mL). The mixturewas stirred at room temperature for 16 h. Further TFA was added (1 mL)and the mixture was stirred at room temperature for 72 h. A saturatedsolution of potassium carbonate was added until pH 9 was reached. Themixture was extracted with dichloromethane and methanol (10:1 mixture).The solution was dried (sodium sulfate) and the solvent was removed invacuum. Silicagel chromatography gave 40 mg of the title compound.

¹H-NMR (300 MHz, DMSO-d₆, detected signals), δ [ppm]=1.34-1.45 (3H),2.11-2.38 (4H), 3.58-3.73 (1H), 4.46 (2H), 5.31-5.46 (1H), 7.01 (1H),7.32 (1H), 7.50 (1H), 8.00 (1H), 8.10-8.18 (2H).

LC-MS (Method 2): R_(t)=0.74 min; MS (ESIpos) m/z=366 [M+H]⁺.

Example 37trans-3-({3-[4-(Propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)cyclobutanamine

At 0° C. 103 mg (0.55 mmol)tert-butyl(trans-3-hydroxycyclobutyl)carbamate were added to 22 mg (0.55mmol) sodium hydride (60% in mineral oil) in 5 mL anhydrous THF. After15 min of stirring on the ice bath, 90 mg (0.27 mmol) of6-chloro-3-[4-(propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazinewere added. The ice bath was removed and the mixture was stirred for 16h at 40° C.

The reaction mixture was poured into half saturated aqueous sodiumchloride solution and extracted with dichloromethane. The organic layerwas dried over sodium sulfate, and concentrated.

The obtained crude material was taken up in 10 mL dichloromethane. 5 mLtrifluoro acetic acid were added am the mixture was stirred for 10 minat room temperature.

5 mL ammonia (25% in water) were carefully added. Half saturated aqueoussodium chloride solution was added. The mixture was extracted withdichlormethane. The organic layer was dried over magnesium sulfate andconcentrated.

The crude material was purified by flash chromatography to give 76 mg ofthe title compound as solid material.

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=1.42 (6H), 2.35-2.43 (2H), 3.70-3.77(1H), 5.46 (2H), 7.04 (1H), 7.33 (1H), 7.54 (1H), 8.04 (1H), 8.16 (1H),8.18 (1H).

LC-MS (Method 3): R_(t)=0.78 min; MS (ESIpos) m/z=380 [M+H]⁺.

Example 38(2R)-1-{[3-(4-Ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-propan-2-amine

To a stirred suspension of (2R)-2-aminopropan-1-ol (48 mg) in anhydrousTHF (6 mL) was added sodium hydride (60% w/w in oil; 42 mg) at 0° C. andthe mixture was stirred at room temperature for 30 min.6-Chloro-3-(4-ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine(100 mg) was added and the mixture was stirred at room temperature for16 h. Ethanol was added carefully, the mixture was stirred for fiveminutes and the solvent was removed in vacuum. Aminophase-silica-gelchromatography followed by silicagel chromatography gave 45 mg of thetitle compound.

1H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.13 (3H), 1.37 (3H), 2.01 (2H),3.31-3.41 (1H), 4.16 (1H), 4.29 (1H), 4.46 (2H), 7.03 (1H), 7.32 (1H),7.45 (1H), 8.01 (1H), 8.11-8.18 (2H).

LC-MS (Method 2): R_(t)=0.76 min; MS (ESIpos) m/z=354 [M+H]⁺.

Example 39tert-Butyl[2-(6-{[(2S)-2-aminopropyl]oxy}imidazo[1,2-b]pyridazin-3-yl)-furo[3,2-c]pyridin-4-yl]ethylcarbamate

To a stirred solution of(2S)-1-[(3-bromoimidazo[1,2-b]pyridazin-6-yl)oxy]propan-2-amine (130 mg)in 1-propanol (13 ml) was added 2M potassium carbonate solution (0.7ml), crude {4-[(tert-Butoxycarbonyl)(ethyl)amino]furo[3,2-c]pyridin-2-yl}boronic acid (70% w/w; 416 mg),triphenylphosphine (12.5 mg) and PdCl₂(PPh₃)₂ (33.5 mg). The mixture washeated to reflux for 1 h. The warm mixture was filtered through Celitethe solvent was removed in vacuum. A half-saturated solution of sodiumbicarbonate was added and the mixture was extracted with a mixture ofdichloromethane and methanol. The organic phase was washed withsaturated sodium chloride solution, dried (sodium sulfate) and thesolvent was removed in vacuum. Silicagel chromatography gave a solidthat was triturated with a mixture of dichloromethane and hexane to give125 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆), δ [ppm]=1.12 (3H), 1.17 (3H), 1.38 (9H), 1.97(2H), 3.30-3.34 (1H), 3.85 (2H), 4.11 (1H), 4.27 (1H), 7.10 (1H), 7.35(1H), 7.63 (1H), 8.17-8.25 (2H), 8.33 (1H).

LC-MS (Method 5): Rt=1.13 min; MS (ESIpos) m/z=453 [M+H]⁺.

Example 402-(6-{[(2S)-2-Aminopropyl]oxy}imidazo[1,2-b]pyridazin-3-yl)-N-ethylfuro[3,2-c]pyridin-4-amine

To a stirred suspension oftert-butyl[2-(6-{[(2S)-2-aminopropyl]oxy}imidazo[1,2-b]pyridazin-3-yl)furo[3,2-c]pyridin-4-yl]ethylcarbamate(115 mg) in dichloromethane (1 mL) was added TFA (0.4 mL). The mixturewas stirred at room temperature for 4 h. The solvent was removed invacuum. The residue was dissolved in dichloromethane and methanol, and asaturated solution of potassium carbonate was added until pH 9 wasreached. The organic phase was separated and dried (sodium sulfate) andthe solvent was removed in vacuum. Silicagel chromatography gave a solidthat was triturated with methanol to give 83 mg of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, detected signals), δ [ppm]=1.13 (3H), 1.20(3H), 1.66 (2H), 3.42-3.53 (2H), 4.24-4.36 (2H), 6.83 (1H), 7.00 (1H),7.10 (1H), 7.68 (1H), 7.87 (1H), 8.05 (1H), 8.12 (1H).

LC-MS (Method 5): R_(t)=0.93 min; MS (ESIpos) m/z=353 [M+H]⁺.

Example 41(2S)-1-({3-[4-(Cyclobutyloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)propan-2-amine

To a stirred solution of 100 mg (0.37 mmol)(2S)-1-[(3-bromoimidazo[1,2-b]-pyridazin-6-yl)oxy]propan-2-amine in 6 mL1-propanol were added 550 μL (1.1 mmol) 2M potassium carbonate solution,344 mg (0.74 mmol)crude[4-(cyclo-butyloxy)furo[3,2-c]pyridin-2-yl]boronic acid (50% w/w),17 mg (15 μmol) tetrakis(triphenylphosphine)palladium(0). The mixturewas heated to reflux for 18 h. The warm mixture was filtered throughCelite and the solvent was removed in vacuum. The mixture was pouredinto water and extracted with dichloromethane. The organic layer wasdried over sodium sulfate and evaporated. The residue was purified byHPLC to yield 29 mg of the title compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.20 (3H), 1.59-1.88 (2H), 2.12 (1H),3.48 (2H), 4.24 (1H), 4.40 (1H), 5.31 (1H), 7.04 (1H), 7.33 (1H), 7.47(1H), 7.99 (1H), 8.12-8.21 (2H), 8.27 (1H).

LC-MS (Method 3): R_(t)=1.27 min; MS (ESIpos) m/z=190 [M+H]⁺⁺.

Example 42(2R)-1-({3-[4-(Cyclobutyloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)propan-2-amine

To a stirred solution of 100 mg (0.37 mmol)(2R)-1-[(3-bromoimidazo[1,2-b]-pyridazin-6-yl)oxy]propan-2-amine in 6 mL1-propanol were added 550 μL (1.1 mmol) 2M potassium carbonate solution,344 mg (0.74 mmol)crude[4-(cyclobutyloxy)furo[3,2-c]pyridin-2-yl]boronic acid (50% w/w),17 mg (15 μmol) tetrakis(triphenylphosphine)palladium(0). The mixturewas heated to reflux for 18 h. The warm mixture was filtered throughCelite and the solvent was removed in vacuum. The mixture was pouredinto water and extracted with dichloromethane. The organic layer wasdried over sodium sulfate and evaporated. The residue was purified byHPLC to yield 32 mg of the title compound as solid material.

¹H-NMR (300 MHz, DMSO-d₆), δ [ppm]=1.20 (3H), 1.59-1.88 (2H), 2.12 (2H),3.48 (2H), 4.24 (1H), 4.40 (1H), 5.31 (1H), 7.04 (1H), 7.33 (1H), 7.47(1H), 7.99 (1H), 8.12-8.21 (2H), 8.27 (1H)

LC-MS (Method 3): R_(t)=1.27 min; MS (ESIpos) m/z=190 [M+H]⁺⁺.

Further, the compounds of formula (I) of the present invention can beconverted to any salt as described herein, by any method which is knownto the person skilled in the art. Similarly, any salt of a compound offormula (I) of the present invention can be converted into the freecompound, by any method which is known to the person skilled in the art.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatine typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatine,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, colouring agents, and flavouring agents such as peppermint, oil ofwintergreen, or cherry flavouring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavouring and colouringagents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more colouring agents; one or more flavouringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al., “Compendium of Excipients forParenteral Formulations” PDA Journal of Pharmaceutical Science aTechnology 1998, 52(5), 238-311; Strickley, R. G “ParenteralFormulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1” PDA Journal of Pharmaceutical Science & Technology1999, 53(6), 324-349; and Nema, S. et al., “Excipients and Their Use inInjectable Products” PDA Journal of Pharmaceutical Science a Technology1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC-CClF₂ and CClF₃)air displacement agents (examples include but are not limited tonitrogen and argon);antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)chelating agents (examples include but are not limited to edetatedisodium and edetic acid)colourants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, DCOrange No. 5, D&C Red No. 8, caramel and ferric oxide red);clarifying agents (examples include but are not limited to bentonite);emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)flavourants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);levigating agents (examples include but are not limited to mineral oiland glycerin);oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)plasticizers (examples include but are not limited to diethyl phthalateand glycerol);solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose); tablet anti-adherents (examples include but arenot limited to magnesium stearate and talc);tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);tablet/capsule opaquants (examples include but are not limited totitanium dioxide);tablet polishing agents (examples include but are not limited to carnubawax and white wax);thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);tonicity agents (examples include but are not limited to dextrose andsodium chloride);viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);andwetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.Lyophilised powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lyophilised powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:50 mg/mL of the desired, water-insoluble compound of this invention5 mg/mL sodium carboxymethylcellulose4 mg/mL TWEEN 809 mg/mL sodium chloride9 mg/mL benzyl alcoholHard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. The present invention relates also to suchcombinations. For example, the compounds of this invention can becombined with known anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof. Otherindication agents include, but are not limited to, anti-angiogenicagents, mitotic inhibitors, alkylating agents, anti-metabolites,DNA-intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzyme inhibitors, toposisomerase inhibitors, biologicalresponse modifiers, or anti-hormones.

In accordance with an embodiment, the present invention relates topharmaceutical combinations comprising:

-   -   one or more first active ingredients selected from a compound of        general formula (I) as defined supra, and    -   one or more second active ingredients selected from        chemotherapeutic anti-cancer agents.

The term “chemotherapeutic anti-cancer agents”, includes but is notlimited to:

131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin,alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin,amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase,azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide,bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel,calcium folinate, calcium levofolinate, capecitabine, carboplatin,carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cetuximab,chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine,clodronic acid, clofarabine, crisantaspase, cyclophosphamide,cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa,dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox,denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine,doxorubicin, doxorubicin+estrone, eculizumab, edrecolomab, elliptiniumacetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol,epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim,fludarabine, fluorouracil, flutamide, formestane, fotemustine,fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin,hydroxycarbamide, 1-125 seeds, ibandronic acid, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferonalfa, interferon beta, interferon gamma, ipilimumab, irinotecan,ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan,letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan,mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methylaminolevulinate, methyltestosterone, mifamurtide, miltefosine,miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide,nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin,oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetinbeta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b,pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide,picibanit, pirarubicin, plerixafor, plicamycin, poliglusam,polyestradiol phosphate, polysaccharide-K, porfimer sodium,pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene,raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid,rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T,sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin,sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin,tegafur, tegafur+gimeracil+oteracil, temoporfin, temozolomide,temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide,thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene,tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin,trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin,vandetanib, vapreotide, vemurafenib, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium-90glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid,zorubicin, or a combination thereof.

The additional pharmaceutical agent can be afinitor, aldesleukin,alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi,altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine,anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin,5-azacytidine, azathioprine, BAY 80-6946, BCG or tice BCG, bestatin,betamethasone acetate, betamethasone sodium phosphate, bexarotene,bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin,campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin,cerubidine, chlorambucil, cisplatin, cladribine, clodronic acid,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, DaunoXome,decadron, decadron phosphate, delestrogen, denileukin diftitox,depo-medrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan,docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard,elitek, ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin,ergamisol, estrace, estradiol, estramustine phosphate sodium, ethinylestradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole,farston, filgrastim, finasteride, fligrastim, floxuridine, fluconazole,fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lapatinib, lentinan sulfate, letrozole, leucovorin,leuprolide, leuprolide acetate, levamisole, levofolinic acid calciumsalt, levothroid, levoxyl, lomustine, lonidamine, marinol,mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrolacetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate,metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide,nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin,picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, RDEA 119, rebif, rhenium-186 etidronate,rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim,semustine, sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-celltherapy, streptozocin, strontium-89 chloride, sunitinib, synthroid,tamoxifen, tamsulosin, tasonermin, tastolactone, taxotere, teceleukin,temozolomide, teniposide, testosterone propionate, testred, thioguanine,thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene,tositumomab, trastuzumab, treosulfan, tretinoin, trexall,trimethylmelamine, trimetrexate, triptorelin acetate, triptorelinpamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine,vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatinstimalamer, zofran, ABI-007, acolbifene, actimmune, affinitak,aminopterin, arzoxifene, asoprisnil, atamestane, atrasentan, sorafenib(BAY 43-9006), avastin, CCI-779, CDC-501, celebrex, cetuximab,crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC,dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide,histamine dihydrochloride, histrelin hydrogel implant, holmium-166DOTMP, ibandronic acid, interferon gamma, intron-PEG, ixabepilone,keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra,lonafarnib, miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6,nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS,osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21,quazepam, R-1549, raloxifene, ranpirnase, 13-cis-retinoic acid,satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin alpha1, tiazofurine, tipifarnib, tirapazamine, TLK-286, toremifene,TransMID-107R, valspodar, vapreotide, vatalanib, verteporfin,vinflunine, Z-100, zoledronic acid or combinations thereof.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11th Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,epothi lone, an epothi lone derivative, etoposide, 5-fluorouracil,hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin,lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate,mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine,raloxifene, streptozocin, tamoxifen, thioguanine, topotecan,vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifene and topotecan.

The compounds of the invention may also be administered in combinationwith protein therapeutics. Such protein therapeutics suitable for thetreatment of cancer or other angiogenic disorders and for use with thecompositions of the invention include, but are not limited to, aninterferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonisticmonoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin,anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab,trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1,bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab,rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35,MT-103, rinfabate, AS-1402, B43-genistein, L-19 basedradioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322,rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine,APC-8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762,lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein,PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab,alpha-particle-emitting radioisotope-linked lintuzumab, EM-1421,HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7,Javelin—prostate cancer, Javelin—melanoma, NY-ESO-1 vaccine, EGFvaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab,zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept,denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonalantibodies useful as the protein therapeutic include, but are notlimited to, muromonab-CD3, abciximab, edrecolomab, daclizumab,gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab,efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab,daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

The compounds of the invention may also be combined with biologicaltherapeutic agents, such as antibodies (e.g. avastin, rituxan, erbitux,herceptin), or recombinant proteins.

In accordance with an embodiment, the present invention relates topharmaceutical combinations comprising:

-   -   one or more compounds of general formula (I), supra, or a        stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a        salt thereof, particularly a pharmaceutically acceptable salt        thereof, or a mixture of same; and    -   one or more agents selected from: a taxane, such as Docetaxel,        Paclitaxel, lapatinib, sunitinib, or Taxol; an epothilone, such        as Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone;        Predinisolone; Dexamethasone; Estramustin; Vinblastin;        Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin;        Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide;        Procarbazine; Melphalan; 5-Fluorouracil; Capecitabine;        Fludarabine; Cytarabine; Ara-C; 2-Chloro-2′-deoxyadenosine;        Thioguanine; an anti-androgen, such as Flutamide, Cyproterone        acetate, or Bicalutamide; Bortezomib; a platinum derivative,        such as Cisplatin, or Carboplatin; Chlorambucil; Methotrexate;        and Rituximab.

The compounds of the invention may also be in combination withantiangiogenesis agents, such as, for example, with avastin, axitinib,DAST, recentin, sorafenib or sunitinib. Combinations with inhibitors ofproteasomes or mTOR inhibitors, or anti-hormones or steroidal metabolicenzyme inhibitors are also possible.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumour or eveneliminate the tumour as compared to administration of either agentalone,(2) provide for the administration of lesser amounts of the administeredchemotherapeutic agents,(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,(5) provide for a higher response rate among treated patients,(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,(7) provide a longer time for tumour progression, and/or(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, a compound of thepresent invention may be used to sensitize a cell to radiation. That is,treatment of a cell with a compound of the present invention prior toradiation treatment of the cell renders the cell more susceptible to DNAdamage and cell death than the cell would be in the absence of anytreatment with a compound of the invention. In one aspect, the cell istreated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the invention incombination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated with one or morecompounds of the invention prior to the treatment of the cell to causeor induce cell death. In one aspect, after the cell is treated with oneor more compounds of the invention, the cell is treated with at leastone compound, or at least one method, or a combination thereof, in orderto cause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In one embodiment, a cell is killed by treating the cell with at leastone DNA damaging agent. That is, after treating a cell with one or morecompounds of the invention to sensitize the cell to cell death, the cellis treated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g., cisplatinum), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In another embodiment, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of the invention isadministered to a cell prior to the radiation or other induction of DNAdamage in the cell. In another aspect of the invention, a compound ofthe invention is administered to a cell concomitantly with the radiationor other induction of DNA damage in the cell. In yet another aspect ofthe invention, a compound of the invention is administered to a cellimmediately after radiation or other induction of DNA damage in the cellhas begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit MKNK-1 and may thereforebe used for the treatment or prophylaxis of diseases of uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses, ordiseases which are accompanied with uncontrolled cell growth,proliferation and/or survival, inappropriate cellular immune responses,or inappropriate cellular inflammatory responses, particularly in whichthe uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses is mediated by MKNK-1, such as, for example,haematological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

In accordance with another aspect therefore, the present inventioncovers a compound of general formula (I), or a stereoisomer, a tautomer,an N-oxide, a hydrate, a solvate, or a salt thereof, particularly apharmaceutically acceptable salt thereof, or a mixture of same, asdescribed and defined herein, for use in the treatment or prophylaxis ofa disease, as mentioned supra.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I), described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the prophylaxis or treatment of a disease.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I) described supra for manufacturing apharmaceutical composition for the treatment or prophylaxis of adisease.

The diseases referred to in the two preceding paragraphs are diseases ofuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, or diseases which are accompanied with uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses,particularly in which the uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses is mediated by MKNK-1, such as, forexample, haematological tumours, solid tumours, and/or metastasesthereof, e.g. leukaemias and myelodysplastic syndrome, malignantlymphomas, head and neck tumours including brain tumours and brainmetastases, tumours of the thorax including non-small cell and smallcell lung tumours, gastrointestinal tumours, endocrine tumours, mammaryand other gynaecological tumours, urological tumours including renal,bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as preferably meaning a response which is less than, orgreater than normal, and which is associated with, responsible for, orresults in, the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases,wherein the diseases are haemotological tumours, solid tumours and/ormetastases thereof.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumours,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumour.

Tumours of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumours of the female reproductiveorgans include, but are not limited to endometrial, cervical, ovarian,vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant mitogen extracellular kinaseactivity, including, but not limited to stroke, heart failure,hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cysticfibrosis, symptoms of xenograft rejections, septic shock or asthma.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of mitogen extracellular kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hydrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumour enlargement and metastasis. Moreover,the growth of new blood and lymph vessels in a tumour provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Preferably, the diseases of said method are haematological tumours,solid tumour and/or metastases thereof.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Biological Assays:

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

MKNK1 Kinase Assay

MKNK1-inhibitory activity of compounds of the present invention wasquantified employing the MKNK1 TR-FRET assay as described in thefollowing paragraphs.

A recombinant fusion protein of Glutathione-S-Transferase (GST,N-terminally) and human full-lengt MKNK1 (amino acids 1-424 and T344D ofaccession number BAA 19885.1), expressed in insect cells usingbaculovirus expression system and purified via glutathione sepharoseaffinity chromatography, was purchased from Carna Biosciences (productno 02-145) and used as enzyme. As substrate for the kinase reaction thebiotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amideform) was used which can be purchased e.g. form the company Biosyntan(Berlin-Buch, Germany).

For the assay 50 nL of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of asolution of MKNK1 in aqueous assay buffer [50 mM HEPES pH 7.5, 5 mMmagnesium chloride, 1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40(Sigma)] was added and the mixture was incubated for 15 min at 22° C. toallow pre-binding of the test compounds to the enzyme before the startof the kinase reaction. Then the kinase reaction was started by theaddition of 3 μL of a solution of adenosine-tri-phosphate (ATP, 16.7μM=>final conc. in the 5 μL assay volume is 10 μM) and substrate (0.1μM=>final conc. in the 5 μL assay volume is 0.06 μM) in assay buffer andthe resulting mixture was incubated for a reaction time of 45 min at 22°C. The concentration of MKNK1 was adjusted depending of the activity ofthe enzyme lot and was chosen appropriate to have the assay in thelinear range, typical concentrations were in the range of 0.05 μg/ml.The reaction was stopped by the addition of 5 μL of a solution ofTR-FRET detection reagents (5 nM streptavidine-XL665 [Cisbio Bioassays,Codolet, France] and 1 nM anti-ribosomal protein S6 (pSer236)-antibodyfrom Invitrogen [#44921G] and 1 nM LANCE EU-W1024 labeled ProteinG[Perkin-Elmer, product no. AD0071]) in an aqueous EDTA-solution (100 mMEDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated for 1 h at 22° C. to allow theformation of complex between the phosphorylated biotinylated peptide andthe detection reagents. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the Eu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm were measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and 1050 values were calculated by a 4 parameter fit.

TABLE 1 MKNK1 IC50s Example MKNK1 IC50 [nM] 1 17 10 34 11 17 12 26 13 52 3 3 11 4 20 5 21 6 23 7 25 8 28 9 48 14 5 15 12 16 8 17 67 18 17 19 1720 64 21 10 22 14 23 32 24 3 25 16 26 100 27 153 28 7 29 8 30 137 31 1332 14 33 99 34 5 35 21 36 4 37 7 38 8 39 250 40 5

MKNK1 Kinase High ATP Assay

MKNK1-inhibitory activity at high ATP of compounds of the presentinvention after their preincubation with MKNK1 was quantified employingthe TR-FRET-based MKNK1 high ATP assay as described in the followingparagraphs.

A recombinant fusion protein of Glutathione-S-Transferase (GST,N-terminally) and human full-length MKNK1 (amino acids 1-424 and T344Dof accession number BAA 19885.1), expressed in insect cells usingbaculovirus expression system and purified via glutathione sepharoseaffinity chromatography, was purchased from Carna Biosciences (productno 02-145) and used as enzyme. As substrate for the kinase reaction thebiotinylated peptide biotin-Ahx-IKKRKLTRRKSLKG (C-terminus in amideform) was used, which can be purchased e.g. from the company Biosyntan(Berlin-Buch, Germany).

For the assay 50 nL of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of asolution of MKNK1 in aqueous assay buffer [50 mM HEPES pH 7.5, 5 mMmagnesium chloride, 1.0 mM dithiothreitol, 0.005% (v/v) Nonidet-P40(Sigma)] was added and the mixture was incubated for 15 min at 22° C. toallow pre-binding of the test compounds to the enzyme before the startof the kinase reaction. Then the kinase reaction was started by theaddition of 3 μL of a solution of adenosine-tri-phosphate (ATP, 3.3mM=>final conc. in the 5 μL assay volume is 2 mM) and substrate (0.1μM=>final conc. in the 5 μL assay volume is 0.06 μM) in assay buffer andthe resulting mixture was incubated for a reaction time of 30 min at 22°C. The concentration of MKNK1 was adjusted depending of the activity ofthe enzyme lot and was chosen appropriate to have the assay in thelinear range, typical concentrations were in the range of 0.003 μg/mL.The reaction was stopped by the addition of 5 μL of a solution ofTR-FRET detection reagents (5 nM streptavidine-XL665 [Cisbio Bioassays,Codolet, France] and 1 nM anti-ribosomal protein S6 (pSer236)-antibodyfrom Invitrogen [#44921G] and 1 nM LANCE EU-W1024 labeled ProteinG[Perkin-Elmer, product no. AD0071]) in an aqueous EDTA-solution (100 mMEDTA, 0.1% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated for 1 h at 22° C. to allow theformation of complex between the phosphorylated biotinylated peptide andthe detection reagents. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the Eu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm were measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (e.g. 20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series preparedseparately before the assay on the level of the 100 fold concentratedsolutions in DMSO by serial dilutions, the exact concentrations may varydepending on the pipettor used) in duplicate values for eachconcentration and IC50 values were calculated by a 4 parameter fit.

TABLE 2 MKNK1 high ATP IC50s Example MKNK1 high ATP IC50 [nM] 1 53 10 6211 59 12 65 13 16 2 5 3 27 4 91 5 65 6 37 7 91 8 136 9 94 14 34 15 31 1619 17 127 18 43 19 34 20 132 21 31 22 79 23 57 24 4 25 28 26 216 27 25928 13 29 16 30 309 31 28 32 37 33 117 34 15 35 44 36 4 37 17 38 23 39593 40 13 41 19 42 26CDK2/CycE kinase assay

CDK2/CycE-inhibitory activity of compounds of the present invention wasquantified employing the CDK2/CycE TR-FRET assay as described in thefollowing paragraphs.

Recombinant fusion proteins of GST and human CDK2 and of GST and humanCycE, expressed in insect cells (Sf9) and purified byGlutathion-Sepharose affinity chromatography, were purchased fromProQinase GmbH (Freiburg, Germany). As substrate for the kinase reactionbiotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amidform) was used which can be purchased e.g. form the company JERINIpeptide technologies (Berlin, Germany).

For the assay 50 nL of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of asolution of CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10mM magnesium chloride, 1.0 mM dithiothreitol, 0.1 mM sodiumortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.Then the kinase reaction was started by the addition of 3 μL of asolution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5μL assay volume is 10 μM) and substrate (1.25 μM=>final conc. in the 5μL assay volume is 0.75 μM) in assay buffer and the resulting mixturewas incubated for a reaction time of 25 min at 22° C. The concentrationof CDK2/CycE was adjusted depending of the activity of the enzyme lotand was chosen appropriate to have the assay in the linear range,typical concentrations were in the range of 130 ng/ml. The reaction wasstopped by the addition of 5 μL of a solution of TR-FRET detectionreagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays, Codolet, France]and 1 nM anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389]and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer,product no. AD0077, as an alternative a Terbium-cryptate-labeledanti-mouse IgG antibody from Cisbio Bioassays can be used]) in anaqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovine serum albumin in100 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC50 values were calculated by a 4 parameter fit.

PDGFRIβ kinase assay

PDGFRβ inhibitory activity of compounds of the present invention wasquantified employing the PDGFRβ HTRF assay as described in the followingparagraphs.

As kinase, a GST-His fusion protein containing a C-terminal fragment ofhuman PDGFRβ (amino acids 561-1106, expressed in insect cells [SF9] andpurified by affinity chromatography, purchased from Proqinase [Freiburgi.Brsg., Germany] was used. As substrate for the kinase reaction thebiotinylated poly-Glu,Tyr (4:1) copolymer (#61GT0BLA) from CisBiointernational (Marcoule, France) was used.

For the assay 50 nL of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of asolution of PDGFRβ in aqueous assay buffer [50 mM HEPES/NaOH pH 7.5, 10mM magnesium chloride, 2.5 mM dithiothreitol, 0.01% (v/v) Triton-X100(Sigma)] were added and the mixture was incubated for 15 min at 22° C.to allow pre-binding of the test compounds to the enzyme before thestart of the kinase reaction. Then the kinase reaction was started bythe addition of 3 μL of a solution of adenosine-tri-phosphate (ATP, 16.7μM=>final conc. in the 5 μL assay volume is 10 μM) and substrate (2.27μg/ml=>final conc. in the 5 μL assay volume is 1.36 μg/ml [˜30 nM]) inassay buffer and the resulting mixture was incubated for a reaction timeof 25 min at 22° C. The concentration of PDGFRβ in the assay wasadjusted depending of the activity of the enzyme lot and was chosenappropriate to have the assay in the linear range, typical enzymeconcentrations were in the range of about 125 pg/μL (final conc. in the5 μL assay volume). The reaction was stopped by the addition of 5 μL ofa solution of HTRF detection reagents (200 nM streptavidine-XLent [CisBiointernational] and 1.4 nM PT66-Eu-Chelate, an europium-chelatelabelled anti-phospho-tyrosine antibody from Perkin Elmer [instead ofthe PT66-Eu-chelate PT66-Tb-Cryptate from Cis Biointernational can alsobe used]) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovineserum albumin in 50 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XLentand the PT66-Eu-Chelate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100 fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit.

Fyn Kinase Assay

C-terminally His6-tagged human recombinant kinase domain of the humanT-Fyn expressed in baculovirus infected insect cells (purchased fromInvitrogen, P3042) was used as kinase. As substrate for the kinasereaction the biotinylated peptide biotin-KVEKIGEGTYGVV (C-terminus inamid form) was used which can be purchased e.g. form the companyBiosynthan GmbH (Berlin-Buch, Germany).

For the assay 50 nL of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of asolution of T-Fyn in aqueous assay buffer [25 mM Tris/HCl pH 7.2, 25 mMmagnesium chloride, 2 mM dithiothreitol, 0.1% (w/v) bovine serumalbumin, 0.03% (v/v) Nonidet-P40 (Sigma)]. were added and the mixturewas incubated for 15 min at 22° C. to allow pre-binding of the testcompounds to the enzyme before the start of the kinase reaction. Thenthe kinase reaction was started by the addition of 3 μL of a solution ofadenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5 μL assayvolume is 10 μM) and substrate (2 μM=>final conc. in the 5 μL assayvolume is 1.2 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 60 min at 22° C. The concentration ofFyn was adjusted depending of the activity of the enzyme lot and waschosen appropriate to have the assay in the linear range, typicalconcentration was 0.13 nM. The reaction was stopped by the addition of 5μL of a solution of HTRF detection reagents (0.2 μM streptavidine-XL[Cisbio Bioassays, Codolet, France) and 0.66 nM PT66-Eu-Chelate, aneuropium-chelate labelled anti-phospho-tyrosine antibody from PerkinElmer [instead of the PT66-Eu-chelate PT66-Tb-Cryptate from CisbioBioassays can also be used]) in an aqueous EDTA-solution (125 mM EDTA,0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.0).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL andthe PT66-Eu-Chelate. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from thePT66-Eu-Chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Normally test compounds were tested on the samemicrotiter plate at 10 different concentrations in the range of 20 μM to1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM, 3.1nM and 1 nM, dilution series prepared before the assay at the level ofthe 100 fold conc. stock solutions by serial 1:3 dilutions) in duplicatevalues for each concentration and IC₅₀ values were calculated by a 4parameter fit.

Flt4 Kinase Assay

Flt4 inhibitory activity of compounds of the present invention wasquantified employing the Flt4 TR-FRET assay as described in thefollowing paragraphs.

As kinase, a GST-His fusion protein containing a C-terminal fragment ofhuman Flt4 (amino acids 799-1298, expressed in insect cells [SF9] andpurified by affinity chromatography, purchased from Proqinase [Freiburgi.Brsg., Germany] was used. As substrate for the kinase reaction thebiotinylated peptide Biotin-Ahx-GGEEEEYFELVKKKK (C-terminus in amideform, purchased from Biosyntan, Berlin-Buch, Germany) was used.

For the assay 50 nL of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of asolution of Flt4 in aqueous assay buffer [25 mM HEPES pH 7.5, 10 mMmagnesium chloride, 2 mM dithiothreitol, 0.01% (v/v) Triton-X100(Sigma), 0.5 mM EGTA, and 5 mM B-phospho-glycerol] were added and themixture was incubated for 15 min at 22° C. to allow pre-binding of thetest compounds to the enzyme before the start of the kinase reaction.Then the kinase reaction was started by the addition of 3 μL of asolution of adenosine-tri-phosphate (ATP, 16.7 μM=>final conc. in the 5μL assay volume is 10 μM) and substrate (1.67 μM=>final conc. in the 5μL assay volume is 1 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 45 min at 22° C. The concentration ofFlt4 in the assay was adjusted depending of the activity of the enzymelot and was chosen appropriate to have the assay in the linear range,typical enzyme concentrations were in the range of about 120 pg/μL(final conc. in the 5 μL assay volume). The reaction was stopped by theaddition of 5 μL of a solution of HTRF detection reagents (200 nMstreptavidine-XL665 [Cis Biointernational] and 1 nM PT66-Tb-Cryptate, anterbium-cryptate labelled anti-phospho-tyrosine antibody from CisbioBioassays (Codolet, France) in an aqueous EDTA-solution (50 mM EDTA,0.2% (w/v) bovine serum albumin in 50 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the PT66-Tb-Cryptate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Tb-Cryptate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100 fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit.

TrkA Kinase Assay

TrkA inhibitory activity of compounds of the present invention wasquantified employing the TrkA HTRF assay as described in the followingparagraphs.

As kinase, a GST-His fusion protein containing a C-terminal fragment ofhuman TrkA (amino acids 443-796, expressed in insect cells [SF9] andpurified by affinity chromatography, purchased from Proqinase [Freiburgi.Brsg., Germany] was used. As substrate for the kinase reaction thebiotinylated poly-Glu,Tyr (4:1) copolymer (#61GT0BLA) from CisBiointernational (Marcoule, France) was used.

For the assay 50 nL of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μL of asolution of TrkA in aqueous assay buffer [8 mM MOPS/HCl pH 7.0, 10 mMmagnesium chloride, 1 mM dithiothreitol, 0.01% (v/v) NP-40 (Sigma), 0.2mM EDTA] were added and the mixture was incubated for 15 min at 22° C.to allow pre-binding of the test compounds to the enzyme before thestart of the kinase reaction. Then the kinase reaction was started bythe addition of 3 μL of a solution of adenosine-tri-phosphate (ATP, 16.7μM=>final conc. in the 5 μL assay volume is 10 μM) and substrate (2.27μg/ml=>final conc. in the 5 μL assay volume is 1.36 μg/ml [˜30 nM]) inassay buffer and the resulting mixture was incubated for a reaction timeof 60 min at 22° C. The concentration of TrkA in the assay was adjusteddepending of the activity of the enzyme lot and was chosen appropriateto have the assay in the linear range, typical enzyme concentrationswere in the range of about 20 pg/μL (final conc. in the 5 μL assayvolume). The reaction was stopped by the addition of 5 μL of a solutionof HTRF detection reagents (30 nM streptavidine-XL665 [CisBiointernational] and 1.4 nM PT66-Eu-Chelate, an europium-chelatelabelled anti-phospho-tyrosine antibody from Perkin Elmer [instead ofthe PT66-Eu-chelate PT66-Tb-Cryptate from Cis Biointernational can alsobe used]) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovineserum albumin in 50 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the bindingof the biotinylated phosphorylated peptide to the streptavidine-XL665and the PT66-Eu-Chelate. Subsequently the amount of phosphorylatedsubstrate was evaluated by measurement of the resonance energy transferfrom the PT66-Eu-Chelate to the streptavidine-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100 fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit.

AlphaScreen SureFire eIF4E Ser209 Phosphorylation Assay

The AlphaScreen SureFire eIF4E Ser209 phoshorylation assay is used tomeasure the phosphorylation of endogenous eIF4E in cellular lysates. TheAlphaScreen SureFire technology allows the detection of phosphorylatedproteins in cellular lysates. In this assay, sandwich antibodycomplexes, which are only formed in the presence of the analyte (p-eIF4ESer209), are captured by AlphaScreen donor and acceptor beads, bringingthem into close proximity. The excitation of the donor bead provokes therelease of singlet oxygen molecules that triggers a cascade of energytransfer in the Acceptor beads, resulting in the emission of light at520-620 nm.

Surefire EIF4e Alphascreen in A549 Cells with 20% FCS Stimulation

For the assay the AlphaScreen SureFire p-eIF4E Ser209 10K Assay Kit andthe AlphaScreen ProteinA Kit (for 10K assay points) both from PerkinElmer were used.

On day one 50.000 A549 cells were plated in a 96-well plate in 100 μLper well in growth medium (DMEM/Hams' F12 with stable Glutamin, 10% FCS)and incubated at 37° C. After attachment of the cells, medium waschanged to starving medium (DMEM, 0.1% FCS, without glucose, withglutamine, supplemented with 5 g/L Maltose). On day two, test compoundswere serially diluted in 50 μL starving medium with a final DMSOconcentration of 1% and were added to A549 cells in test plates at afinal concentration range from as high 10 μM to as low 10 nM dependingon the activities of the tested compounds. Treated cells were incubatedat 37° C. for 2 h. 37 ul FCS was added to the wells (=final FCSconcentration 20%) for 20 min. Then medium was removed and cells werelysed by adding 50 μL lysis buffer. Plates were then agitated on a plateshaker for 10 min. After 10 min lysis time, 4 μL of the lysate istransferred to a 384 well plate (Proxiplate from Perkin Elmer) and 5 μLReaction Buffer plus Activation Buffer mix containing AlphaScreenAcceptor beads was added. Plates were sealed with TopSeal-A adhesivefilm, gently agitated on a plate shaker for 2 hours at room temperature.Afterwards 2 μL Dilution buffer with AlphaScreen Donor beads were addedunder subdued light and plates were sealed again with TopSeal-A adhesivefilm and covered with foil. Incubation takes place for further 2 hgently agitation at room temperature. Plates were then measured in anEnVision reader (Perkin Elmer) with the AlphaScreen program. Each datapoint (compound dilution) was measured as triplicate.

The 1050 values were determined by means of a 4-parameter fit.

It will be apparent to persons skilled in the art that assays for otherMKNK-1 kinases may be performed in analogy using the appropriatereagents.

Thus the compounds of the present invention effectively inhibit one ormore MKNK-1 kinases and are therefore suitable for the treatment orprophylaxis of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses, particularly in which theuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses is mediated by MKNK-1, more particularly in which the diseasesof uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses are haemotological tumours, solid tumours and/ormetastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

1. A compound of general formula (I):

in which:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule; R1 represents a linear C₂-C₆-alkyl-, a branchedC₃-C₆-alkyl-, or a C₃-C₆-cycloalkyl group which is optionallysubstituted with one or more substituents selected, independently fromeach other, from: a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 6-memberedheterocycloalkyl which is connected as spiro; aryl- optionallysubstituted one or more times, independently from each other, with an Rsubstituent; aryl-C₁-C₆-alkyloxy- optionally substituted one or moretimes, independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group; R2 represents a hydrogenatom; R3 represents a substituent selected from: a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,—C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂, —NHR′, —N(R′)R″,—N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂, —N(H)C(═O)NHR′,—N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″,—N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′,—N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH, C₁-C₆-haloalkoxy-,C₃-C₆-cycloalkoxy-, C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-, —OC(═O)R′, —SH,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″ group; R4 represents a substituent selected from: ahydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-memberedheterocycloalkyl-, aryl-optionally substituted one or more times,independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂,—OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,—S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″ group; R represents asubstituent selected from: a halogen atom, a —CN, C₁-C₆-alkyl-,C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3-to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R′,—C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′,—N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂, —N(H)C(═O)NHR′,—N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″,—N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′,—N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH, C₁-C₆-haloalkoxy-,—OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from: C₁-C₆-alkyl-, C₁-C₆-haloalkyl-; n represents an integerof 0, 1, 2 or 3; or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, or a mixture of same.
 2. The compoundaccording to claim 1, wherein:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule; R1 represents a linear C₂-C₆-alkyl-, a branchedC₃-C₆-alkyl-, or a C₃-C₆-cycloalkyl group which is optionallysubstituted with one or more substituents selected, independently fromeach other, from: a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 6-memberedheterocycloalkyl which is connected as spiro; aryl- optionallysubstituted one or more times, independently from each other, with an Rsubstituent; aryl-C₁-C₆-alkyloxy- optionally substituted one or moretimes, independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —OH,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′,—OC(═O)N(R′)R″, —SH, C₁-C₆-alkyl-S— group; R2 represents a hydrogenatom; R3 represents a substituent selected from: a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,—C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —NH₂, —NHR′, —N(R′)R″,—N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂, —N(H)C(═O)NHR′,—N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″,—N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′,—N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH, C₁-C₆-haloalkoxy-,C₃-C₆-cycloalkoxy-, C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-, —OC(═O)R′, —SH,—S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″,—S(═O)(═NR′)R″ group; R4 represents a substituent selected from: ahydrogen atom, a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl,C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl- group; R represents a substituentselected from: a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-memberedheterocycloalkyl-, aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂,—C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OR′, —NH₂, —NHR′, —N(R′)R″,—N(H)C(═O)R′, —N(R′)C(═O)R′, —N(H)C(═O)NH₂, —N(H)C(═O)NHR′,—N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂, —N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″,—N(H)C(═O)OR′, —N(R′)C(═O)OR′, —NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′,—N(H)S(═O)₂R′, —N(R′)S(═O)₂R′, —N═S(═O)(R′)R″, —OH, C₁-C₆-haloalkoxy-,—OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, —S(═O)R′,—S(═O)₂R′, —S(═O)₂NH₂, —S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group;R′ and R″ represent, independently from each other, a substituentselected from: C₁-C₆-alkyl-, C₁-C₆-haloalkyl-; n represents an integerof 0, 1, 2 or 3; or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, or a mixture of same.
 3. The compoundaccording to claim 1, wherein:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule; R1 represents a linear C₂-C₆-alkyl-, a branchedC₃-C₆-alkyl-, or a C₃-C₆-cycloalkyl group which is optionallysubstituted with one or more substituents selected, independently fromeach other, from: a halogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₂-C₆-alkenyl-, C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 6-memberedheterocycloalkyl which is connected as spiro; aryl- optionallysubstituted one or more times, independently from each other, with an Rsubstituent; aryl-C₁-C₆-alkyloxy- optionally substituted one or moretimes, independently from each other, with an R substituent; heteroaryl-optionally substituted one or more times, independently from each other,with an R substituent; —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″, —C(═O)OH,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′, —OH,C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂, —OC(═O)NHR′, —OC(═O)N(R′)R″,—SH, C₁-C₆-alkyl-S— group; R2 represents a hydrogen atom; R3 representsa substituent selected from: a halogen atom, a —CN, —NHR′, —OH,C₁-C₆-haloalkoxy-, C₃-C₆-cycloalkoxy-, C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-group; R4 represents a substituent selected from: a hydrogen atom, ahalogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₃-C₁₀-cycloalkyl-,aryl-, heteroaryl- group; R represents a substituent selected from: ahalogen atom, a —CN, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-,C₂-C₆-alkynyl-, C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-,aryl-, heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂,—OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,—S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group; R′ and R″ represent,independently from each other, a substituent selected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-; n represents an integer of 0 or 1; or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, or a mixture of same.
 4. The compound according to claim 1,wherein:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule; R1 represents a linear C₂-C₆-alkyl-, a branchedC₃-C₆-alkyl-, or a C₃-C₆-cycloalkyl group which is optionallysubstituted with one or more substituents selected, independently fromeach other, from: a halogen atom, a —CN, C₁-C₃-alkyl-, C₁-C₃-haloalkyl-,C₃-C₆-cycloalkyl-, 3- to 6-membered heterocycloalkyl which is connectedas spiro; aryl- optionally substituted one or two times, independentlyfrom each other, with an R substituent; aryl-C₁-C₆-alkyloxy- optionallysubstituted one or more times, independently from each other, with an Rsubstituent; heteroaryl- optionally substituted one or two times,independently from each other, with an R substituent; —C(═O)NH₂, —NH₂,—NHR′, —N(R′)R″, —OH, C₁-C₃-haloalkoxy-; R2 represents a hydrogen atom;R3 represents a substituent selected from: a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, —NHR′, —OH, C₁-C₆-haloalkoxy-,C₃-C₆-cycloalkoxy-, C₃-C₆-cycloalkyl-C₁-C₃-alkoxy- group; R4 representsa substituent selected from: a hydrogen atom, a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₃-C₁₀-cycloalkyl-, aryl-, heteroaryl-group; R represents a substituent selected from: a halogen atom, a —CN,C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₂-C₆-alkenyl-, C₂-C₆-alkynyl-,C₃-C₁₀-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-,heteroaryl-, —C(═O)R′, —C(═O)NH₂, —C(═O)N(H)R′, —C(═O)N(R′)R″,—C(═O)OR′, —NH₂, —NHR′, —N(R′)R″, —N(H)C(═O)R′, —N(R′)C(═O)R′,—N(H)C(═O)NH₂, —N(H)C(═O)NHR′, —N(H)C(═O)N(R′)R″, —N(R′)C(═O)NH₂,—N(R′)C(═O)NHR′, —N(R′)C(═O)N(R′)R″, —N(H)C(═O)OR′, —N(R′)C(═O)OR′,—NO₂, —N(H)S(═O)R′, —N(R′)S(═O)R′, —N(H)S(═O)₂R′, —N(R′)S(═O)₂R′,—N═S(═O)(R′)R″, —OH, C₁-C₆-haloalkoxy-, —OC(═O)R′, —OC(═O)NH₂,—OC(═O)NHR′, —OC(═O)N(R′)R″, —SH, —S(═O)R′, —S(═O)₂R′, —S(═O)₂NH₂,—S(═O)₂NHR′, —S(═O)₂N(R′)R″, —S(═O)(═NR′)R″group; R′ and R″ represent,independently from each other, a substituent selected from:C₁-C₆-alkyl-, C₁-C₆-haloalkyl-; n represents an integer of 0 or 1; or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, or a mixture of same.
 5. The compound according to claim 1,wherein:

represents a group selected from:

wherein * indicates the point of attachment of said groups with the restof the molecule; R1 represents a linear C₂-C₆-alkyl-, a branchedC₃-C₆-alkyl-, or a C₃-C₆-cycloalkyl group, which is optionallysubstituted with one or more substituents selected, independently fromeach other, from: a 3- to 6-membered heterocycloalkyl which is connectedas spiro; aryl- optionally substituted one or two times, independentlyfrom each other, with an R substituent; aryl-C₁-C₆-alkyloxy- optionallysubstituted one or more times, independently from each other, with an Rsubstituent; R2 represents a hydrogen atom; R3 represents a substituentselected from: a C₁-C₆-alkoxy-, C₃-C₆-cycloalkoxy-,C₃-C₆-cycloalkyl-C₁-C₃-alkoxy-, —NHR′, —OH group; R4 represents ahydrogen atom; n represents an integer of 0 or 1; or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of same.
 6. The compound according to claim 1, which is selectedfrom the group consisting of:(1S)-2-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-phenylethanamine;trans-3-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutanamine;(2R)-1-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;(1S)-2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-phenylethanamine;(2S)-1-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;(2R)-2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-1-amine;(1R)-2-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-phenylethanamine;(2R)-2-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-1-amine;(1R)-2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-1-phenylethanamine;(2R,3R)-3-(Benzyloxy)-1-{[3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}butan-2-amine;(2R)-1-(Benzyloxy)-3-{[3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;(2S)-1-{[3-(Furo[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;trans-3-{[3-(Furo[2,3-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutanaminesalt with formic acid;trans-3-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutanaminesalt with formic acid;(2R)-2-Amino-3-{[3-(4-methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}propan-1-ol;3-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylpropan-1-amine;(2R)-1-{[3-(Furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;(1S,3R)-3-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}cyclopentanamine;(2S)-1-({3-[4-(Propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)propan-2-amine;(2S)-1-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;trans-4-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]-oxy}cyclohexanaminesalt with formic acid;1-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-methylpropan-2-amine;3-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-2-phenylpropan-1-amine;trans-3-({3-[4-(2,2-Dimethylpropoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)cyclobutanamine;(2S)-1-({3-[4-(Cyclopropylmethoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)propan-2-amine;(2R)-1-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;1-[3-({[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-methyl)oxetan-3-yl]methanamine;trans-3-{[3-(Furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutanamine;trans-3-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}cyclobutanamine;(2S)-1-{[3-(Furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-3-methylbutan-2-amine;(1S,2S)-2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-cyclopentanamine;(2S)-1-{[3-(4-Ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;2-{[3-(4-Methoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-3-phenylpropan-1-amine;(2S)-1-({3-[4-(2,2-Dimethylpropoxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)propan-2-amine;2-{6-[(trans-3-Aminocyclobutyl)oxy]imidazo[1,2-b]pyridazin-3-yl}furo[3,2-c]pyridin-4-ol;trans-3-{[3-(4-Ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}-cyclobutanamine;trans-3-({3-[4-(Propan-2-yloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}oxy)cyclobutanamine;(2R)-1-{[3-(4-Ethoxyfuro[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl]oxy}propan-2-amine;tert-Butyl[2-(6-{[(2S)-2-aminopropyl]oxy}imidazo[1,2-b]pyridazin-3-yl)furo[3,2-c]-pyridin-4-yl]ethylcarbamate;2-(6-{[(2S)-2-Aminopropyl]oxy}imidazo[1,2-b]pyridazin-3-yl)-N-ethylfuro[3,2-c]pyridin-4-amine;(2S)-1-({3-[4-(Cyclobutyloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}-oxy)propan-2-amine;and(2R)-1-({3-[4-(Cyclobutyloxy)furo[3,2-c]pyridin-2-yl]imidazo[1,2-b]pyridazin-6-yl}-oxy)propan-2-amine.7. A method of preparing a compound of general formula (I) according toclaim 1, said method comprising the step of allowing an intermediatecompound of general formula (V):

in which A, R2, R3, R4 and n are as defined in claim 1, and X representsa leaving group, such as a halogen atom, for example a chlorine, bromineor iodine atom, or a perfluoroalkylsulfonate group for example, such asa trifluoromethylsulfonate group or a nonafluorobutylsulfonate group,for example, to react with a compound of general formula (III):

in which R1 is defined in claim 1, thereby giving a compound of generalformula (I):

in which A, R2, R3, R4 and n are as defined in claim
 1. 8. (canceled) 9.A pharmaceutical composition comprising a compound of general formula(I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, ora pharmaceutically acceptable salt thereof, or a mixture of same,according to claim 1, and a pharmaceutically acceptable diluent orcarrier.
 10. A pharmaceutical combination comprising: one or more firstactive ingredients selected from a compound of general formula (I)according to claim 1, and one or more second active ingredients selectedfrom chemotherapeutic anti-cancer agents and target-specific anti-canceragents.
 11. (canceled)
 12. (canceled)
 13. A method for the prophylaxisof or treatment of a disease of uncontrolled cell growth, proliferationand/or survival, an inappropriate cellular immune response, or aninappropriate cellular inflammatory response, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of general formula (I), or a stereoisomer, a tautomer, anN-oxide, a hydrate, a solvate, or a pharmaceutically acceptable saltthereof, or a mixture of same, according to claim
 1. 14. A compound ofgeneral formula (V):

in which A, R2, R3, R4 and n are as defined in claim 1, and X representsa leaving group, such as a halogen atom, for example a chlorine, bromineor iodine atom, or a perfluoroalkylsulfonate group for example, such asa trifluoromethylsulfonate group or a nonafluorobutylsulfonate group,for example.
 15. (canceled)
 16. The method according to claim 13,wherein the uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune response, or inappropriate cellularinflammatory response is mediated by the MKNK-1 pathway.
 17. The methodaccording to claim 13, wherein the disease of uncontrolled cell growth,proliferation and/or survival, inappropriate cellular immune response,or inappropriate cellular inflammatory response is a haematologicaltumour, a solid tumour or metastases thereof.
 18. The method accordingto claim 17, wherein the haematological tumour, solid tumour ormetastases thereof is selected from leukaemias and myelodysplasticsyndrome, malignant lymphomas, head and neck tumours, brain tumours andbrain metastases, tumours of the thorax, non-small cell and small celllung tumours, gastrointestinal tumours, endocrine tumours, mammary andother gynaecological tumours, urological tumours, renal, bladder andprostate tumours, skin tumours, and sarcomas, or metastases thereof.